Compounds and methods

ABSTRACT

Disclosed is a compound having the formula: 
     
       
         
         
             
             
         
       
         
         
           
             pharmaceutically acceptable salts or solvates thereof and pharmaceutical compositions containing the same, wherein the structural variables are as defined herein. The compounds, salts and solvates of this invention are useful as LXR agonists.

This application is a 371 of International Application No.PCT/US03/09450, filed 26 Mar. 2003, which claims the benefit of U.S.Provisional Application No. 60/368,425, filed 27 Mar. 2002.

FIELD OF THE INVENTION

The present invention relates to compounds useful as modulating agentsfor liver X receptors (LXR). Additionally, the present invention relatedto pharmaceutical formulations comprising such compounds, and thetherapeutic use of the same.

BACKGROUND OF THE INVENTION

LXR is a transcription factor. The orphan nuclear receptors, LXRα andLXRβ (collectively LXR) play a role in the maintenance of cholesterolbalance. Peet et al., Curr. Opin. Genet. Dev. 8:571-575 (1998). Inaddition, LXR binds to the ATP Binding Cassette Transporter-1 (ABCA1)gene and increases expression of the gene to result in increased ABCA1protein. ABCA1 is a membrane bound transport protein that is involved inthe regulation of cholesterol efflux from extrahepatic cells ontonascent HDL particles. Mutations in the ABCA1 gene are responsible forgenetic diseases that result in the complete absence or low levels ofHDL cholesterol and a concomitant highly increased risk ofcardiovascular disease. See Brooks-Wilson et al., Nat. Genet. 22:336-345(1999); Bodzioch et al., Nat Genet. 22: 347-351 (1999); and Rust et al.,Nat. Genet. 22:352-355 (1999). ABCA1 knockout mice homozygous for themutation in the ABCA1 gene have virtually no plasma HDL, whereas theheterozygotes produce 50% of the HDL of wild type animals. See, Orso etal., Nat. Genet. 24:192-196 (2000) and McNeish et al., Proc. Natl. Acad.Sci. USA 97:4245-4250 (2000). ABCA1 knockout mice also show increasedcholesterol absorption. See, McNeish et al., Proc. Natl. Acad. Sci. USA97:4245-4250 (2000). Increased expression of ABCA1 results in increasedHDL cholesterol, decreased absorption of cholesterol, and increasedremoval of excess cholesterol from extrahepatic tissues, includingmacrophages. LXR agonists also upregulate macrophage expression ofapolipoprotein E and ABCG1, both of which contribute to the efflux ofcellular cholesterol. By stimulating macrophage cholesterol effluxthrough upregulation of ABCA1, ABCG1, and apoE expression, as well asincreasing the expression of other target genes including cholesterylester transfer protein and lipoprotein lipase, LXR agonists influenceplasma lipoproteins.

Accordingly, compounds which function as LXR modulating agents, andparticularly as LXR agonists, would be useful in methods of increasingABCA1, ABCG1, and apolipoprotein E expression, increasing cholesterolefflux from peripheral cells, and treating LXR mediated diseases andconditions such as cardiovascular disease and Inflammation.

SUMMARY OF THE INVENTION

This invention is directed to a compound of Formula I:

wherein:

X is selected from C₁-C₈ alkyl, halo, —OR¹⁰, —NR¹⁴R¹⁵, nitro, cyano,—COOR¹⁰, —COR¹³, —OCOR¹³, —N(R¹⁷)COR¹³, —N(R¹⁷)CONR¹⁴R¹⁵, —N(R¹⁷)COOR¹³,—SO₃H, —SO₂NR¹⁴R¹⁵, —C(═NR¹⁷)NR¹⁴R¹⁵, —N(R¹⁷)SO₂R¹⁶, and a 5 or6-membered heterocyclic group;

or X and an adjacent R³, taken together with the atoms to which they arebonded, form an alkylenedioxy moiety;

Z is CH, CR³ or N, wherein when Z is CH or CR³, k is 0-4 and t is 0 or1, and when Z is N, k is 0-3 and t is 0;

Y is selected from —O—, —S—, —N(R¹⁰)—, and —C(R⁴)(R⁵)—;

W¹ is selected from C₁-C₆ alkyl, C₃-C₈ cycloalkyl, aryl and Het, whereinsaid C₁-C₈ alkyl, C₃-C₈ cycloalkyl, Ar and Het are optionallyunsubstituted or substituted with one or more groups independentlyselected from halo, cyano, nitro, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆alkynyl, —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆ alkyl-C(O)SR¹⁰, —C₀-C₆alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆ alkyl-NR¹¹R¹², —C₀-C₆alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-SO₃H, —C₀-C₆alkyl-SO₂NR¹¹R¹², —C₀-C₆ alkyl-SO₂R¹⁰, —C₀-C₆ alkyl-SOR¹³, —C₀-C₆alkyl-OCOR¹³, —C₀-C₆ alkyl-OC(O)NR¹¹R¹², —C₀-C₆ alkyl-OC(O)OR¹³, —C₀-C₆alkyl-NR¹¹C(O)OR¹³, —C₀-C₆ alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₆alkyl-NR¹¹COR¹³, where said C₁-C₆ alkyl, is optionally unsubstituted orsubstituted by one or more halo substituents;

W² is selected from H, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,—C₀-C₆ alkyl-NR¹¹R¹², —C₀-C₆ alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆alkyl-CO₂R¹⁰, —C₀-C₆ alkyl-C(O)SR¹⁰, —C₀-C₆ alkyl-CONR¹¹R¹², —C₀-C₆alkyl-COR¹³, —C₀-C₆ alkyl-OCOR¹³, —C₀-C₆ alkyl-OCONR¹¹R¹², —C₀-C₆alkyl-NR¹¹CONR¹¹R¹², —C₀-C₆ alkyl-NR¹¹COR¹³, —C₀-C₆ alkyl-Het, —C₀-C₆alkyl-Ar and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl, wherein said C₁-C₆ alkyl isoptionally unsubstituted or substituted by one or more halosubstituents, and wherein the C₃-C₇ cycloalkyl, Ar and Het moieties ofsaid —C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-Ar and —C₀-C₆ alkyl-C₃-C₇ cycloalkylare optionally unsubstituted or substituted with one or more groupsindependently selected from halo, cyano, nitro, C₁-C₆ alkyl, C₃-C₆alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆ alkyl-C(O)SR¹⁰,—C₀-C₆ alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆ alkyl-NR¹¹R¹², —C₀-C₆alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-SO₃H, —C₀-C₆alkyl-SO₂NR¹¹R¹², —C₀-C₆ alkyl-SO₂R¹⁰, —C₀-C₆ alkyl-SOR¹³, —C₀-C₆alkyl-OCOR¹³, —C₀-C₆ alkyl-OC(O)NR¹¹R¹², —C₀-C₆ alkyl-OC(O)OR¹³, —C₀-C₆alkyl-NR¹¹C(O)OR¹³, —C₀-C₆ alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₆alkyl-NR¹¹COR¹³, where said C₁-C₆ alkyl, is optionally unsubstituted orsubstituted by one or more halo substituents;

W³ is selected from the group consisting of: H, halo, C₁-C₆ alkyl,—C₀-C₆ alkyl-NR¹¹R¹², —C₀-C₆ alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆alkyl-CO₂R¹⁰, —C₀-C₆ alkyl-C(O)SR¹⁰, —C₀-C₆ alkyl-CONR¹¹R¹², —C₀-C₆alkyl-COR¹³, —C₀-C₆ alkyl-OCOR¹³, —C₀-C₆ alkyl-OCONR¹¹R¹², —C₀-C₆alkyl-NR¹¹CONR¹¹R¹², —C₀-C₆ alkyl-NR¹¹COR¹³, —C₀-C₆ alkyl-Het, —C₁-C₆alkyl-Ar and —C₁-C₆ alkyl-C₃-C₇ cycloalkyl, wherein said C₁-C₆ alkyl isoptionally unsubstituted or substituted by one or more halosubstituents;

Q is selected from C₃-C₈ cycloalkyl, Ar and Het; wherein said C₃-C₈cycloalkyl, Ar and Het are optionally unsubstituted or substituted withone or more groups independently selected from halo, cyano, nitro, C₁-C₆alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆alkyl-C(O)SR¹¹, —C₀-C₆ alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆alkyl-NR¹¹R¹², —C₀-C₆ alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-SO₃H,—C₀-C₆alkyl-SO₂NR¹¹R¹², —C₀-C₆ alkyl-SO₂R¹⁰, —C₀-C₆ alkyl-SOR¹³, —C₀-C₆alkyl-OCOR¹³, —C₀-C₆ alkyl-OC(O)NR¹¹R¹², —C₀-C₆ alkyl-OC(O)OR¹³, —C₀-C₆alkyl-NR¹¹C(O)OR¹³, —C₀-C₆ alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₆alkyl-NR¹¹COR¹³, where said C₁-C₆ alkyl is optionally unsubstituted orsubstituted by one or more halo substituents;

p is 0-8;

n is 2-8;

m is 0 or 1;

q is 0 or 1;

t is 0 or 1;

each R¹ and R² are independently selected from H, halo, C₁-C₆ alkyl,C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-NR¹¹R¹², —C₀-C₆ alkyl-OR¹⁰,—C₀-C₆ alkyl-SR¹⁰, —C₁-C₆ alkyl-Het, —C₁-C₆ alkyl-Ar and —C₁-C₆alkyl-C₃-C₇ cycloalkyl, or R¹ and R² together with the carbon to whichthey are attached form a 3-5 membered carbocyclic or heterocyclic ring,wherein said heterocyclic ring contains one, or more heteroatomsselected from N, O, and S, where any of said C₁-C₆ alkyl is optionallyunsubstituted or substituted by one or more halo substituents;

each R³ is the same or different and is independently selected fromhalo, cyano, nitro, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆alkyl-Ar, —C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-C₃-C₇ cycloalkyl, —C₀-C₆alkyl-CO₂R¹⁰, —C₀-C₆ alkyl-C(O)SR¹⁰, —C₀-C₆ alkyl-CONR¹¹R¹², —C₀-C₆alkyl-COR¹³, —C₀-C₆ alkyl-NR¹¹R¹², —C₀-C₆ alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰,—C₀-C₆ alkyl-SO₃H, —C₀-C₆ alkyl-SO₂NR¹¹R¹², —C₀-C₆ alkyl-SO₂R¹⁰, —C₀-C₆alkyl-SOR¹³, —C₀-C₆ alkyl-OCOR¹³, —C₀-C₆ alkyl-OC(O)NR¹¹R¹², —C₀-C₆alkyl-OC(O)OR¹³, —C₀-C₆ alkyl-NR¹¹C(O)OR¹³, —C₀-C₆ and —C₀-C₆alkyl-NR¹¹COR¹³, wherein said C₁-C₆ alkyl is optionally unsubstituted orsubstituted by one or more halo substituents;

each R⁴ and R⁵ is independently selected from H, halo, C₁-C₆ alkyl,—C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-Ar and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl;

R⁶ and R⁷ are each independently selected from H, halo, C₁-C₆ alkyl,—C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-Ar and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl;

R⁸ and R⁹ are each independently selected from H, halo, C₁-C₆ alkyl,—C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-Ar and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl;

R¹⁰ is selected from H, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl,—C₀-C₆ alkyl-Ar, —C₀-C₆ alkyl-Het and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl;

each R¹¹ and each R¹² are independently selected from H, C₁-C₆ alkyl,C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-Ar, —C₀-C₆ alkyl-Het and—C₀-C₆ alkyl-C₃-C₇ cycloalkyl, or R¹¹ and R¹² together with the nitrogento which they are attached form a 4-7 membered heterocyclic ring whichoptionally contains one or more additional heteroatoms selected from N,O, and S;

R¹³ is selected from C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆alkyl-Ar, —C₀-C₆ alkyl-Het and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl;

R¹⁴ and R¹⁵ are each independently selected from H, C₁-C₆ alkyl, C₃-C₆alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-Ar, —C₀-C₆ alkyl-Het, —C₀-C₆alkyl-C₃-C₇ cycloalkyl, —C₀-C₆ alkyl-O—Ar, —C₀-C₆ alkyl-O-Het, —C₀-C₆alkyl-O—C₃-C₇ cycloalkyl, —C₀-C₆ alkyl-S(O)_(x)—C₁-C₆ alkyl, —C₀-C₆alkyl-S(O)_(x)—Ar, —C₀-C₆ alkyl-S(O)_(x)-Het, —C₀-C₆alkyl-S(O)_(x)—C₃-C₇ cycloalkyl, —C₀-C₆ alkyl-NH-Het, —C₀-C₆alkyl-NH—C₃-C₇ cycloalkyl, —C₀-C₆ alkyl-N(C₁-C₄ alkyl)-Ar, —C₀-C₆alkyl-N(C₁-C₄ alkyl)-Het, —C₀-C₆ alkyl-N(C₁-C₄ alkyl)-C₃-C₇ cycloalkyl,—C₀-C₆ alkyl-Ar, —C₀-C₆ alkyl-Het and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl,where x is 0, 1 or 2, or R¹⁴ and R¹⁵, together with the nitrogen towhich they are attached, form a 4-7 membered heterocyclic ring whichoptionally contains one or more additional heteroatoms selected from N,O, and S, wherein said C₁-C₆ alkyl is optionally substituted by one ormore of the substituents independently selected from the group halo,—OH, —SH, —NH₂, —NH(unsubstituted C₁-C₆ alkyl), —N(unsubstituted C₁-C₆alkyl)(unsubstituted C₁-C₆ alkyl), unsubstituted —OC₁-C₆ alkyl, —CO₂H,—CO₂(unsubstituted C₁-C₆ alkyl), —CONH₂, —CONH(unsubstituted C₁-C₆alkyl), —CON(unsubstituted C₁-C₆ alkyl)(unsubstituted C₁-C₆ alkyl),—SO₃H, —SO₂NH₂, —SO₂NH(unsubstituted C₁-C₆ alkyl) and—SO₂N(unsubstituted C₁-C₆ alkyl)(unsubstituted C₁-C₆ alkyl);

R¹⁶ is C₁-C₆ alkyl, —C₀-C₆ alkyl-Ar or —C₀-C₆ alkyl-Het; and

R¹⁷ is H, C₁-C₆ alkyl, —C₀-C₆ alkyl-Ar or —C₀-C₆ alkyl-Het;

provided that X is not COOR¹⁰ when Y is —O—, p is 0-8, n is 2-8, m is 1,q is 0 or 1, t is 0, each R¹ and R² is independently selected from H,C₁-C₆ alkyl, —OH, —OC₁-C₆ alkyl, —SH, and —SC₁-C₆ alkyl, each R⁴, R⁵,R⁶, R⁷, R⁵ and R⁹ are independently H or C₁-C₄ alkyl, k is 0 or 1, W³ isH. W¹ and W² are each independently selected from C₃-C₈ cycloalkyl andaryl and R³ and Q are as defined above; or

provided that the compound is not

-   5-[3-[[(3,4-dichlorophenyl)methyl][2-(2-naphthalenyl)ethyl]amino]propoxy]-3-methoxy-1,2-benzenedicarboxylic    acid-   5-[3-[[(3,4-dichlorophenyl)methyl][2-(2-naphthalenyl)ethyl]amino]propoxy]-3-methoxy-1,2-benzenedicarboxylic    acid, dimethyl ester-   4-[[[2-(4-carboxyphenoxy)ethyl][2-[2-[(5-phenylpentyl)oxy]phenyl]ethyl]amino]methyl]benzoic    acid-   4-[[[2-[4-(ethoxycarbonyl)phenoxy]ethyl][2-[2-(octyloxy)phenyl]ethyl]amino]methyl]-benzoic    acid methyl ester,-   4-[[[2-(4-carboxyphenoxy)ethyl][2-[2-(octyloxy)phenyl]ethyl]amino]methyl],    benzoic acid,-   α-[[[3-(4-fluorophenyl)-1,1-dimethylpropyl](phenylmethyl)amino]methyl]-3-(phenylmethoxy)-benzenemethanol    hydrochloride,-   N-[2-(4-amino-3,5-dichlorophenyl)ethyl]-4-fluoro-N-(phenylmethyl)-benzenepropanamine    monohydrochloride,-   N-[2-(4-amino-3,5-dichlorophenyl)ethyl]4-chloro-N-(phenylmethyl)-benzenepropanamine    monohydrochloride,-   4-amino-3,5-dichloro-α-[[[3-(4-fluorophenyl)propyl](phenylmethyl)amino]methyl]-benzenemethanol    monohydrochloride,-   4-amino-3,5-dichloro-α-[[[3-(4-chlorophenyl)propyl](phenylmethyl)amino]methyl]-benzenemethanol    monohydrochloride,-   2-chloro-5-[2-[[3-(4-fluorophenyl)-1-methylpropyl](phenylmethyl)amino]-1-hydroxyethyl]-benzamide    monohydrochloride,-   4-[2-[[2-hydroxy-2-[4-(phenylmethoxy)phenyl]ethyl](phenylmethyl)amino]ethoxy]-benzeneacetamide,-   4-[2-[[2-[3,4-bis(phenylmethoxy)phenyl]ethyl](phenylmethyl)amino]ethoxy]-benzenesulfonamide    monohydrochloride,-   (R)-3-(phenylmethoxy)-α-[[[3-[3-(phenylmethoxy)phenyl]propyl](phenylmethyl)amino]methyl]-benzenemethanol-   2,2-dichloro-acetic acid    (R){benzyl-[3-(3-benzyloxy-phenyl)-propyl]-amino)(3-benzyloxy-phenyl)-ethyl    ester,-   3-amino-α-[[[3-(3,4-dimethoxyphenyl)-1-methylpropyl](phenylmethyl)amino]methyl]-4-(phenylmethoxy)-benzenemethanol,-   α-[[[3-(3,4-dimethoxyphenyl)-1-methylpropyl](phenylmethyl)amino]methyl]-3-nitro-4-(phenylmethoxy)-benzenemethanol,-   α-[[[3-(3,4-dimethoxyphenyl)-1-methylpropyl](phenylmethyl)amino]methyl]-3-nitro-5-(phenylmethoxy)-benzenemethanol,-   3-amino-α-[[[3-(3,4-dimethoxyphenyl)-1-methylpropyl](phenylmethyl)amino]methyl]-5(phenylmethoxy)-benzenemethanol,    or-   4-[2-[[2-(4-fluorophenoxy)ethyl](phenylmethyl)amino]ethyl]-1-piperazineacetic    acid ethyl ester,

or a pharmaceutically acceptable salt or solvate thereof.

This invention is also directed to methods for the prevention ortreatment of an LXR mediated disease or condition comprisingadministering a therapeutically effective amount of a compound havingFormula I-A:

wherein:

X is selected from C₁-C₈ alkyl, halo, —OR¹⁰, —NR¹⁴R¹⁵, nitro, cyano,—COOR¹⁰, —COR¹³, —OCOR¹³, —N(R¹⁷)COR¹³, —N(R¹⁷)CONR¹⁴R¹⁵, —N(R¹⁷)COOR¹³,—SO₃H, —SO₂NR¹⁴R¹⁵, —C(═NR¹⁷)NR¹⁴R¹⁵, —N(R¹⁷)SO₂R¹⁶, and a 5 or6-membered heterocyclic group;

or X and an adjacent R³, taken together with the atoms to which they arebonded, form an alkylenedioxy moiety;

Z is CH, CR³ or N, wherein when Z is CH or CR³, k is 0-4 and t is 0 or1, and when Z is N, k is 0-3 and t is 0;

Y is selected from —O—, —S—, —N(R¹⁰)—, and —C(R⁴)(R⁵)—;

W¹ is selected from C₁-C₆ alkyl, C₃-C₈ cycloalkyl, aryl and Het, whereinsaid C₁-C₈ alkyl, C₃-C₈ cycloalkyl, Ar and Het are optionallyunsubstituted or substituted with one or more groups independentlyselected from halo, cyano, nitro, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆alkynyl, —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆ alkyl-C(O)SR¹⁰, —C₀-C₆alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆ alkyl-NR¹¹R¹², —C₀-C₆alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-SO₃H, —C₀-C₆alkyl-SO₂NR¹¹R¹², —C₀-C₆ alkyl-SO₂R¹⁰, —C₀-C₆ alkyl-SOR¹³, —C₀-C₆alkyl-OCOR¹³, —C₀-C₆ alkyl-OC(O)NR¹¹R¹², —C₀-C₆ alkyl-OC(O)OR¹³, —C₀-C₆alkyl-NR¹¹C(O)OR¹³, —C₀-C₆ alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₆alkyl-NR¹¹COR¹³, where said C₁-C₆ alkyl, is optionally unsubstituted orsubstituted by one or more halo substituents;

W² is selected from H, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,—C₀-C₆ alkyl-NR¹¹R¹², —C₀-C₆ alkyl-SR¹⁰, —C₁-C₆ alkyl-OR¹⁰, —C₀-C₆alkyl-CO₂R¹⁰, —C₀-C₆ alkyl-C(O)SR¹⁰, —C₀-C₆ alkyl-CONR¹¹R¹², —C₀-C₆alkyl-COR¹³, —C₀-C₆ alkyl-OCOR¹³, —C₀-C₆ alkyl-OCONR¹¹R², —C₀-C₆alkyl-NR¹¹CONR¹¹R¹², —C₀-C₆ alkyl-NR¹¹COR¹³, —C₀-C₆ alkyl-Het, —C₀-C₆alkyl-Ar and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl, wherein said C₁-C₆ alkyl isoptionally unsubstituted or substituted by one or more halosubstituents, and wherein the C₃-C₇ cycloalkyl, Ar and Het moieties ofsaid —C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-Ar and —C₀-C₆ alkyl-C₃-C₇ cycloalkylare optionally unsubstituted or substituted with one or more groupsindependently selected from halo, cyano, nitro, C₁-C₆ alkyl, C₃-C₆alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆ alkyl-C(O)SR¹⁰,—C₀-C₆ alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆ alkyl-NR¹¹R¹², —C₀-C₆alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-SO₃H, —C₀-C₆alkyl-SO₂NR¹¹R¹², —C₀-C₆ alkyl-SO₂R¹⁰, —C₀-C₆ alkyl OR¹³, —C₀-C₆alkyl-OCOR¹³, C₀-C₆ alkyl-OC(O)NR¹¹R¹², —C₀-C₆ alkyl-OC(O)OR¹³, —C₀-C₆alkyl-NR¹¹C(O)OR¹³, —C₀-C₆ alkyl-NR¹¹C(O)NR¹¹R¹² and —C₀-C₆alkyl-NR¹¹COR¹³, where said C₁-C₆ alkyl, is optionally unsubstituted orsubstituted by one or more halo substituents;

W³ is selected from the group consisting of: H, halo, C₁-C₆ alkyl,—C₀-C₆ alkyl-NR¹¹R¹², —C₀-C₆ alkyl-SR¹¹, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆alkyl-CO₂R¹⁰, —C₀-C₆ alkyl-C(O)SR¹⁰, —C₀-C₆ alkyl-CONR¹¹R¹², —C₀-C₆alkyl-COR¹³, —C₀-C₆ alkyl-OCOR¹³, —C₀-C₆ alkyl-OCONR¹¹R¹², —C₀-C₆alkyl-NR¹¹CONR¹¹R¹², —C₀-C₆ alkyl-NRCOR¹³, —C₀-C₆ alkyl-Het, —C₁-C₆alkyl-Ar and —C₁-C₆ alkyl-C₃-C₇ cycloalkyl, wherein said C₁-C₆ alkyl isoptionally unsubstituted or substituted by one or more halosubstituents;

Q is selected from C₃-C₈ cycloalkyl, Ar and Het; wherein said C₃-C₈cycloalkyl, Ar and Het are optionally unsubstituted or substituted withone or more groups independently selected from halo, cyano, nitro, C₁-C₆alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-CO₂R′″, —C₀-C₆alkyl-C(O)SR¹⁰, —C₀-C₆ alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆alkyl-NR¹¹R¹², —C₀-C₆ alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-SO₃H,—C₀-C₆ alkyl-NR¹¹R¹², —C₀-C₆ alkyl-SO₂R¹⁰, —C₀-C₆ alkyl-SOR¹³, —C₀-C₆alkyl-OCOR¹³, —C₀-C₆ alkyl-OC(O)NR¹¹R¹², —C₀-C₆ alkyl-OC(O)OR¹³, —C₀-C₆alkyl-NR¹¹C(O)OR¹³, —C₀-C₆ alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₆alkyl-NR¹¹COR¹³, where said C₁-C₆ alkyl is optionally unsubstituted orsubstituted by one or more halo substituents;

p is 0-8;

n is 2-8;

m is 0 or 1;

q is 0 or 1;

t is 0 or 1;

each R¹ and R² are independently selected from H, halo, C₁-C₆ alkyl,C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-NR¹¹R¹², —C₀-C₆ alkyl-OR¹⁰,—C₀-C₆ alkyl-SR¹⁰, —C₁-C₆ alkyl-Het, —C₁-C₆ alkyl-Ar and —C₁-C₆alkyl-C₃-C₇ cycloalkyl, or R¹ and R² together with the carbon to whichthey are attached form a 3-5 membered carbocyclic or heterocyclic ring,wherein said heterocyclic ring contains one, or more heteroatomsselected from N, O, and S, where any of said C₁-C₆ alkyl is optionallyunsubstituted or substituted by one or more halo substituents;

each R³ is the same or different and is independently selected fromhalo, cyano, nitro, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆alkyl-Ar, —C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-C₃-C₇ cycloalkyl, —C₀-C₆alkyl-CO₂R¹⁰, —C₀-C₆ alkyl-C(O)SR¹⁰, —C₀-C₆ alkyl-CONR¹¹R¹², —C₀-C₆alkyl-COR¹³, —C₀-C₆ alkyl-NR¹¹R¹², —C₀-C₆ alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰,—C₀-C₆ alkyl-SO₃H, —C₀-C₆ alkyl-SO₂NR¹¹R¹², —C₀-C₆ alkyl-SO₂R¹⁰, —C₀-C₆alkyl-SOR¹³, —C₀-C₆ alkyl-OCOR¹³, —C₀-C₆ alkyl-OC(O)NR¹¹R¹³, —C₀-C₆alkyl-OC(O)OR¹³, —C₀-C₆ alkyl-NR¹¹C(O)OR¹³, —C₀-C₆alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₆ alkyl-NR¹¹COR¹³, wherein said C₁-C₆alkyl is optionally unsubstituted or substituted by one or more halosubstituents;

each R⁴ and R⁵ is independently selected from H, halo, C₁-C₆ alkyl,—C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-Ar and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl;

R⁶ and R⁷ are each independently selected from H, halo, C₁-C₆ alkyl,—C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-Ar and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl;

R⁸ and R⁹ are each independently selected from H, halo, C₁-C₆ alkyl,—C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-Ar and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl;

R¹⁰ is selected from H, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl,—C₀-C₆ alkyl-Ar, —C₀-C₆ alkyl-Het and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl;

each R¹¹ and each R¹² are independently selected from H, C₁-C₆ alkyl,C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-Ar, —C₀-C₆ alkyl-Het and—C₀-C₆ alkyl-C₃-C₇ cycloalkyl, or R¹¹ and R¹² together with the nitrogento which they are attached form a 4-7 membered heterocyclic ring whichoptionally contains one or more additional heteroatoms selected from N,O, and S;

R¹³ is selected from C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆alkyl-Ar, —C₀-C₆ alkyl-Het and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl;

R¹⁴ and R¹⁵ are each independently selected from H, C₁-C₆ alkyl, C₃-C₆alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-Ar, —C₀-C₆ alkyl-Het, —C₀-C₆alkyl-C₃-C₇ cycloalkyl, —C₀-C₆ alkyl-O—Ar, —C₀-C₆ alkyl-O-Het, —C₀-C₆alkyl-O—C₃-C₇ cycloalkyl, —C₀-C₆ alkyl-S(O)_(x)—C₁-C₆ alkyl, —C₀-C₆alkyl-S(O)_(x)—Ar, —C₀-C₆ alkyl-S(O)_(x)-Het, —C₀-C₆alkyl-S(O)_(x)—C₃-C₇ cycloalkyl, —C₀-C₆ alkyl-NH-Het, —C₀-C₆alkyl-NH—C₃-C₇ cycloalkyl, —C₀-C₆ alkyl-N(C₁-C₄ alkyl)-Ar, —C₀-C₆alkyl-N(C₁-C₄ alkyl)-Het, —C₀-C₆ alkyl-N(C₁-C₄ alkyl)-C₃-C₇ cycloalkyl,—C₀-C₆ alkyl-Ar, —C₀-C₆ alkyl-Het and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl,where x is 0, 1 or 2, or R¹⁴ and R¹⁵, together with the nitrogen towhich they are attached, form a 4-7 membered heterocyclic ring whichoptionally contains one or more additional heteroatoms selected from N,O, and S, wherein said C₁-C₆ alkyl is optionally substituted by one ormore of the substituents independently selected from the group halo,—OH, —SH, —NH₂, —NH(unsubstituted C₁-C₆ alkyl), —N(unsubstituted C₁-C₆alkyl)(unsubstituted C₁-C₆ alkyl), unsubstituted —OC₁-C₆ alkyl, —CO₂H,—CO₂(unsubstituted C₁-C₆ alkyl), —CONH₂, —CONH(unsubstituted C₁-C₆alkyl), —CON(unsubstituted C₁-C₆ alkyl)(unsubstituted C₁-C₆ alkyl),—SO₃H, —SO₂NH₂, —SO₂NH(unsubstituted C₁-C₆ alkyl) and—SO₂N(unsubstituted C₁-C₈ alkyl)(unsubstituted C₁-C₆ alkyl);

R¹⁶ is C₁-C₆ alkyl, —C₀-C₆ alkyl-Ar or —C₀-C₆ alkyl-Het; and

R¹⁷ is H, C₁-C₆ alkyl, —C₀-C₆ alkyl-Ar or —C₀-C₆ alkyl-Het;

provided that X is not COOR¹⁰ when Y is —O—, p is 0-8, n is 2-8, m is 1,q is 0 or 1, t is 0, each R¹ and R² is independently selected from H,C₁-C₆ alkyl, —OH, —O—C₁-C₆ alkyl, —SH, and —S—C₁-C₆ alkyl, each R⁴, R⁵,R⁶, R⁷, R⁸ and R⁹ are independently H or C₁-C₄ alkyl, k is 0 or 1, W³ isH, W¹ and W² are each independently selected from C₃-C₈ cycloalkyl andaryl and R³ and Q are as defined above;

or a pharmaceutically acceptable salt or solvate thereof.

Also included within the scope of this invention are methods forpreparing compounds of this invention, or pharmaceutically acceptablesalts or solvates thereof.

Unless otherwise provided, each alkyl, alkoxy, alkenyl, alkynyl,cycloalkyl, aryl or Het (including any 3-5-membered, 4-7-membered,56-membered or 5-7-membered carbocyclic or heterocyclic rings or ringmoieties) herein is independently unsubstituted or substituted with oneore more substituents defined hereinbelow.

LXR mediated diseases or conditions include inflammation, cardiovasculardisease and atherosclerosis. Accordingly, the methods of this inventionfurther comprise methods for increasing reverse cholesterol transport,inhibiting cholesterol absorption, and decreasing inflammation. Thepresent invention also provides pharmaceutical compositions comprising acompound of this invention.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “alkyl” represents a straight-or branched-chainsaturated hydrocarbon, containing 1 to 10 carbon atoms, unless otherwiseprovided, which may be unsubstituted or substituted by one or more ofthe substituents described below. Exemplary alkyls include, but are notlimited to methyl (Me), ethyl (Et), n-propyl, isopropyl, n-butyl,isobutyl, t-butyl, n-pentyl, neopentyl and hexyl and structural isomersthereof. Any “alkyl” herein may be optionally substituted by one or moreof the substituents independently selected from the group halo, —OH,—SH, —NH₂, —NH(unsubstituted C₁-C₆ alkyl), —N(unsubstituted C₁-C₆alkyl)(unsubstituted C₁-C₆ alkyl), unsubstituted —OC₁-C₆ alkyl, —CO₂H,and —CO₂(unsubstituted C₁-C₆ alkyl).

When combined with another substituent term (e.g., aryl or cycloalkyl asin -alkyl-Ar or -alkyl-cycloalkyl), the “alkyl” term therein refers toan alkylene moiety, that is, an unsubstituted divalent straight-orbranched-chain saturated hydrocarbon moiety, containing 1 to 10 carbonatoms, unless otherwise provided. For example, the term “—C₀-C₆alkyl-Ar”, where C is 1-6 is intended to mean the radical -alkyl-aryl(e.g., —CH₂-aryl or —CH(CH₃)-aryl) and is represented by the bondingarrangement present in a benzyl group. The term “C₀ alkyl” in a moiety,such as —C₀-C₆ alkyl-Ar or —O—(C₀-C₆ alkyl)-Ar, provides for noalkyl/alkylene group being present in the moiety. Thus, when C is zero,—C₀-C₆ alkyl-Ar is equivalent to —Ar and —O-(C₀-C₆ alkyl)-Ar isequivalent to —O—Ar.

As used herein, the term “alkenyl” represents a straight-orbranched-chain hydrocarbon, containing 2 to 10 carbon atoms, unlessotherwise provided, and one or more carbon-carbon double bonds. Alkenylgroups may be unsubstituted or substituted by one or more of thesubstituents described below. Exemplary alkenyls include, but are notlimited ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl,isobutenyl, butadienyl, pentenyl and hexenyl and structural isomersthereof. Both cis (Z) and trans (E) isomers of each double bond that maybe present in the compounds of this invention are included within thescope of this invention. Any “alkenyl” herein may be optionallysubstituted by one or more of the substituents independently selectedfrom the group halo, —OH, —SH, —NH₂, —NH(unsubstituted C₁-C₆ alkyl),—N(unsubstituted C₁-C₆ alkyl)(unsubstituted C₁-C₆ alkyl), unsubstituted—OC₁-C₆ alkyl, —CO₂H, and —CO₂(unsubstituted C₁-C₆ alkyl).

As used herein, the term “alkynyl” represents a straight-orbranched-chain hydrocarbon, containing 2 to 10 carbon atoms, unlessotherwise provided, and one or more carbon-carbon triple bonds and,optionally, one or more carbon-carbon double bonds. Both cis (Z) andtrans (E) isomers of each double bond that may be present in thecompounds of this invention are included within the scope of thisinvention. Exemplary alkynyls include, but are not limited ethynyl,propynyl (propargyl, isopropynyl), 1-butynyl, 2-butynyl, 3-butynyl,pentynyl and hexynyl and structural isomers thereof. Any “alkynyl”herein may be optionally substituted by one or more of the substituentsindependently selected from the group halo, —OH, —SH, —NH₂,—NH(unsubstituted C₁-C₆ alkyl), —N(unsubstituted C₁-C₆alkyl)(unsubstituted C₁-C₆ alkyl), unsubstituted —OC₁-C₆ alkyl, —CO₂H,and —CO₂(unsubstituted C₁-C₆ alkyl).

For the purposes of this invention, when an alkenyl or alkynyl group isa substituent on an oxygen, nitrogen or sulfur atom (e.g., as in oxy(—OR), thio (—SR), ester (—CO₂R or —C(O)SR), amino (—NRR) or amido(—CONRR) moieties and the like), it is understood that a double ortriple bond of the alkenyl or alkynyl group is not located on carbonsthat are α,β to the oxygen, nitrogen or sulfur atom. Compoundscontaining ene-amino or enol-type moieties (—NR—CR═CR— or —O—CR═CR—) arenot intended to be included within the scope of this invention.

“Cycloalkyl” represents a non-aromatic monocyclic, bicyclic, ortricyclic hydrocarbon containing from 3 to 10 carbon atoms which may beunsubstituted or substituted by one or more of the substituentsdescribed below and may be saturated or partially unsaturated. Exemplarycycloalkyls include monocyclic rings having from 3-7, preferably 36,carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl andcycloheptyl. Any “cycloalkyl” herein may be optionally substituted byone or more of the substituents independently selected from the grouphalo, cyano, C₁-C₆ alkyl (which specifically includes C₁-C₆ haloalkyl,—C₀-C₆ alkyl-OH, —C₀-C₆ alkyl-SH and —C₀-C₆ alkyl-NR′R″), C₃-C₆ alkenyl,oxo, —OC₁-C₆alkyl, —OC₁-C₆ alkenyl, —C₀-C₆ alkyl-COR′, —C₀-C₆alkyl-CO₂R′, —C₀-C₆ alkyl-CONR′R″, —OC₀-C₆ alkyl-CO₂H, —OC₂-C₆alkyl-NR′R″, and —C₀-C₆ alkyl-SO₂NR′R″, wherein each R′ and R″ areindependently selected from H and unsubstituted C₁-C₆ alkyl.

The terms “Ar” or “aryl” as used herein interchangeably at alloccurrences mean a substituted or unsubstituted carbocyclic aromaticgroup, which may be optionally fused to another carbocyclic aromaticgroup moiety or to a cycloalkyl group moiety, which may be optionallysubstituted or unsubstituted. Examples of suitable Ar or aryl groupsinclude phenyl, naphthyl indenyl, 1-oxo-1H-indenyl andtetrahydronaphthyl. Any “Ar”, “aryl” or “phenyl” herein may beoptionally unsubstituted or substituted by one or more of thesubstituents independently selected from the group halo, cyano, C₁-C₆alkyl (which specifically includes C₁-C₆ haloalkyl, —C₀-C₆ alkyl-OH,—C₀-C₆ alkyl-SH and —C₀-C₆ alkyl-NR′R″), C₃-C₆ alkenyl, —OC₁-C₆alkyl,—OC₁-C₆ alkenyl, —C₀-C₆ alkyl-COR′, —C₀-C₆ alkyl-CO₂R′, —C₀-C₆alkyl-CONR′R″, —OC₀-C₆ alkyl-CO₂H, —OC₂-C₆ alkyl-NR′R″, —C₀-C₆alkyl-C(═NR′)NR′R″, and —C₀-C₆ alkyl-SO₂NR′R″, wherein each R′ and R″are independently selected from H and unsubstituted C₁-C₆ alkyl.

The term “Het” as used herein means a stable 5- to 7-memberedmonocyclic, a stable 7- to 10-membered bicyclic, or a stable 11- to18-membered tricyclic heterocyclic ring group, all of which aresaturated, unsaturated or aromatic, and consist of carbon atoms and fromone to three heteroatoms selected from N, O and S, and which includesbicyclic and tricyclic rings containing one or more fused cycloalkyl,aryl (e.g., phenyl) or heteroaryl (aromatic Het) ring moieties. As usedherein the term “Het is also intended to encompass heterocyclic groupscontaining nitrogen and/or sulfur where the nitrogen or sulfurheteroatoms are optionally oxidized or the nitrogen heteroatom isoptionally quaternized. The heterocyclic group may be attached at anyheteroatom or carbon atom that results in the creation of a stablestructure. Any “Het” herein may be optionally unsubstituted orsubstituted by one or more of the substituents independently selectedfrom the group halo, cyano, C₁-C₆ alkyl (which specifically includesC₀-C₆ haloalkyl, —C₀-C₆ alkyl-OH, —C₀-C₆ alkyl-SH and —C₀-C₆alkyl-NR′R″), C₃-C₆ alkenyl, oxo, —OC₁-C₆alkyl, —OC₁-C₆ alkenyl, —C₀-C₆alkyl-COR′, —C₀-C₆ alkyl-CO₂R′, —C₀-C₆ alkyl-CONR′R″, —OC₀-C₆alkyl-CO₂H, —OC₂-C₆ alkyl-NR′R″, —C₀-C₆ alkyl-C(═NR′)NR′R″ and —C₀-C₆alkyl-SO₂NR′R″, wherein each R′ and R″ are independently selected from Hand unsubstituted C₁-C₆ alkyl.

Examples of such heterocyclic groups include, but are not limited topiperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolodinyl, 2-oxoazepinyl, azepanyl, pyrrolyl, 4-piperidonyl,pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, pyridinyl,pyrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, morpholinyl,thiazolidinyl, thiazolinyl, thiazolyl, 1,3-benzodioxolyl (e.g.,methylenedioxy-substituted phenyl), 1,4-benzodioxolyl, quinuclidinyl,indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,benzoxazolyl, furyl, pyranyl, tetrahydrofuryl, tetrahydropyranyl,thienyl, benzoxazolyl, benzofuranyl, benzothienyl, dihydrobenzofuranyl,dihydrobenzothienyl, dihydroindolyl, tetrazolyl, thiamorpholinylsulfoxide, thiamorpholinyl sulfone, and oxadiazolyl, as well astriazolyl, thiadiazolyl, oxadiazolyl, isoxazolyl, isothiazolyl,imidazolyl, pyridazinyl, pyrimidinyl and triazinyl which are availableby routine chemical synthesis and are stable.

Examples of the 4-7 membered heterocyclic rings useful in the compoundsof this invention, include, but are not limited to azetidinyl,piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolodinyl, azepanyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl,pyrazolyl, pyrazolidinyl, imidazolyl, pyridinyl, pyrazinyl,oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, morpholinyl,thiazolidinyl, thiazolinyl, thiazolyl, furyl, pyranyl, tetrahydrofuryl,tetrahydropyranyl, thienyl, tetrazolyl, thiamorpholinyl sulfoxide,thiamorpholinyl sulfone, and oxadiazolyl, as well as triazolyl,thiadiazolyl, oxadiazolyl, isoxazolyl, isothiazolyl, imidazolyl,pyridazinyl, pyrimidinyl and triazinyl which are available by routinechemical synthesis and are stable. The 4-7 membered heterocyclic groupmay be optionally unsubstituted or substituted by one or more of thesubstituents independently selected from the group halo, cyano, C₁-C₆alkyl (which specifically includes C₀-C₆ haloalkyl, —C₀-C₆ alkyl-OH,—C₀-C₆ alkyl-SH and —C₀-C₆ alkyl-NR′R″), C₃-C₆ alkenyl, oxo,—OC₁-C₆alkyl, —OC₁-C₅ alkenyl, —C₀-C₆ alkyl-COR′, —C₀-C₆ alkyl-CO₂R′,—C₀-C₆ alkyl-CONR′R″, —OC₀-C₆ alkyl-CO₂H, —OC₂-C₆ alkyl-NR′R″, —C₀-C₆alkyl-C(═NR′)NR′R″ and —C₀-C₆ alkyl-SO₂NR′R″, wherein each R′ and R″ areindependently selected from H and unsubstituted C₁-C₆ alkyl.

Examples of 5 or 6 membered heterocyclic groups include, but are notlimited to piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolodinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl,pyrazolidinyl, imidazolyl, pyridinyl, pyrazinyl, oxazolidinyl,oxazolinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolidinyl,thiazolinyl, thiazolyl, furyl, pyranyl, tetrahydrofuryl,tetrahydropyranyl, thienyl, tetrazolyl, thiamorpholinyl sulfoxide,thiamorpholinyl sulfone, and oxadiazolyl, as well as triazolyl,thiadiazolyl, oxadiazolyl, isoxazolyl, isothiazolyl, imidazolyl,pyridazinyl, pyrimidinyl and triazinyl which are available by routinechemical synthesis and are stable. The 5-6 membered heterocyclic groupmay be attached at any heteroatom or carbon atom that results in thecreation of a stable structure. The 5-6 membered heterocyclic group maybe optionally unsubstituted or substituted by one or more of thesubstituents independently selected from the group halo, cyano, C₁-C₆alkyl (which specifically includes C₁-C₆ haloalkyl, —C₀-C₆ alkyl-OH,—C₀-C₆ alkyl-SH and —C₀-C₆ alkyl-NR′R″), C₃-C₆ alkenyl, oxo, —OC₁-C₆alkyl, —OC₁-C₆ alkenyl, —C₀-C₆ alkyl-COR′, —C₀-C₆ alkyl-CO₂R′, —C₀-C₆alkyl-CONR′R″, —OC₀-C₆ alkyl-CO₂H, —OC₂-C₆ alkyl-NR′R″, —C₀-C₆alkyl-C(═NR′)NR′R″ and —C₀-C₆ alkyl-SO₂NR′R″, wherein each R′ and R″ areindependently selected from H and unsubstituted C₁-C₆ alkyl.

The terms “halogen” and “halo” represent chloro, fluoro, bromo or iodosubstituents. “Alkoxy” is intended to mean the radical —OR_(a), whereR_(a) is an alkyl group, wherein alkyl is as defined above, providedthat —O—C₁ alkyl may be optionally substituted by one or more of thesubstituents independently selected from the group halo and —CO₂H.Exemplary alkoxy groups include methoxy, ethoxy, propoxy, and the like.“Phenoxy” is intended to mean the radical —OR_(ar), where R_(ar) is aphenyl group. “Acetoxy” is intended to mean the radical —O—C(═O)-methyl.“Benzoyloxy” is intended to mean the radical —O—C(═O)-phenyl.“Alkylenedioxy” is intended to mean the divalent radical —OR_(a)O— whichis bonded to adjacent atoms (e.g., adjacent atoms on a phenyl ornaphthyl ring), wherein R_(a) is a lower alkyl group. “Oxo” is intendedto mean the keto diradical ═O, such as present on a pyrrolidin-2-onering.

If a substituent described herein is not compatible with the syntheticmethods of this invention, the substituent may be protected with asuitable protecting group that is stable to the reaction conditions usedin these methods. The protecting group may be removed at a suitablepoint in the reaction sequence of the method to provide a desiredintermediate or target compound. Suitable protecting groups and themethods for protecting and de-protecting different substituents usingsuch suitable protecting groups are well known to those skilled in theart; examples of which may be found in T. Greene and P. Wuts, ProtectingGroups in Chemical Synthesis (3rd ed.), John Wiley & Sons, NY (1999),which is incorporated herein by reference in its entirety. In someinstances, a substituent may be specifically selected to be reactiveunder the reaction conditions used in the methods of this invention.Under these circumstances, the reaction conditions convert the selectedsubstituent into another substituent that is either useful as anintermediate compound in the methods of this invention or is a desiredsubstituent in a target compound.

The term “pharmaceutically acceptable salt” is intended to describe asalt that retains the biological effectiveness of the free acid or baseof a specified compound and is not biologically or otherwiseundesirable.

If an inventive compound is a base, a desired salt may be prepared byany suitable method known in the art, including treatment of the freebase with an inorganic acid, such as hydrochloric acid, hydrobromicacid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid,metaphosphoric acid and the like, or with an organic acid, such asacetic acid, trifluoroacetic acid, formic acid, maleic acid, lacticacid, succinic acid, mandelic acid, fumaric acid, malonic acid, malicacid, pyruvic acid, oxalic acid, glycolic acid, citric acid, tartaricacid, gluconic acid, glutaric acid, lactobionic, orotic, cholic, apyranosidyl acid, such as glucuronic acid or galacturonic acid, an aminoacid, such as aspartic acid or glutamic acid, an aromatic acid, such asbenzoic acid, salicylic acid, cinnamic acid, pamoic acid or1-hydroxy-2-naphthoic acid, a sulfonic acid, such as benzenesulfonicacid, p-toluenesulfonic acid, naphthalenesulfonic acid, methanesulfonicacid, ethanesulfonic acid or the like. Additional examples ofpharmaceutically acceptable salts include sulfates, pyrosulfates,bisulfates, sulfites, bisulfites, phosphates, chlorides, bromides,iodides, acetates, propionates, decanoates, caprylates, acrylates,formates, isobutyrates, caproates, heptanoates, propiolates, oxalates,malonates succinates, suberates, sebacates, fumarates, maleates,butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates,methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates,phthalates, phenylacetates, phenylpropionates, phenylbutrates, citrates,lactates, γ-hydroxybutyrates, glycollates, tartrates mandelates, andsulfonates, such as xylenesulfonates, methanesulfonates,propanesulfonates, naphthalene-1-sulfonates andnaphthalene-2-sulfonates. Embodiments of a pharmaceutically acceptablesalts (e.g., hydrochloride salts, dihydrochloride salts,methanesulfonate salts, dimethanesulfonate salts and trifluoroaceticacid salts) of the compounds of this invention are provided in theExamples.

If an inventive compound is an acid, a desired salt may be prepared byany suitable method known to the art, including treatment of the freeacid with an excess of an inorganic or organic alkaline reagent.Illustrative examples of suitable salts include salts derived fromammonia; primary, secondary, tertiary amines (including secondary andtertiary cyclic amines), such as ethylene diamine, dicyclohexylamine,ethanolamine, piperidine, morpholine, and piperazine; salts derived fromamino acids such as glycine and arginine; as well as salts derived froman alkali metal, alkaline earth metal, or ammonium hydroxide, carbonate,alkoxide or sulfate, such as sodium hydroxide, sodium carbonate, sodiumbicarbonate, sodium sulfate, etc., and corresponding alkaline saltscontaining, for example, Li⁺, K⁺, Ca⁺⁺, Mg⁺⁺ and NH₄ ⁺ cations.

The term “solvate” is intended to mean a pharmaceutically acceptablesolvate form of a specified compound of this invention, or a saltthereof, that retains the biological effectiveness of such compound.Examples of solvates include compounds of the invention in combinationwith water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, aceticacid, or ethanolamine. In the case of compounds, salts, or solvates thatare solids, it is understood by those skilled in the art that theInventive compounds, salts, or solvates may exist in different crystalforms, all of which are intended to be within the scope of the presentinvention and specified formulas.

Because the compounds of this invention may contain both acid and basemoieties, pharmaceutically acceptable salts may be prepared by treatingthese compounds with an alkaline reagent or an acid reagent,respectively. Accordingly, this invention also provides for theconversion of one pharmaceutically acceptable salt of a compound of thisinvention, e.g., a hydrochloride salt, into another pharmaceuticallyacceptable salt of a compound of this invention, e.g., a mesylate saltor a sodium salt.

Also included within the scope of this invention are prodrugs of thecompounds of this invention. The ester compounds of this invention,wherein X is other than —OH, may be considered prodrugs. Such estercompounds may be converted to compounds that are active as LXRmodulators and may be, themselves, active as LXR modulators. The term“prodrug” is intended to mean a compound that is converted underphysiological conditions, e.g., by solvolysis or metabolically, to acompound according to this invention that is pharmaceutically active. Aprodrug may be a derivative of one of the compounds of this inventionthat contains a carboxylic or phosphoric acid ester or amide moiety thatmay be cleaved under physiological conditions. A prodrug containing sucha moiety may be prepared according to conventional procedures, forexample, by treatment of a compound of this invention containing anamino, amido or hydroxyl moiety with a suitable derivatizing agent, forexample, a carboxylic or phosphoric acid halide or acid anhydride, or byconverting a carboxyl moiety of a compound of this invention to an esteror amide. Prodrugs of the compounds of this invention may be determinedusing techniques known in the art, for example, through metabolicstudies. See, e.g., “Design of Prodrugs,” (H. Bundgaard, Ed.) 1985,Elsevier Publishers B. V., Amsterdam, The Netherlands.

It will be appreciated by those skilled in the art that the compounds ofthis invention may exist in different tautomeric forms. All tautomericforms of the compounds described herein are intended to be encompassedwithin the scope of the present invention.

The compounds of this invention may contain at least one chiral centerand may exist as single stereoisomers (e.g., single enantiomers),mixtures of stereoisomers (e.g., any mixture of enantiomers ordiastereomers) or racemic mixtures thereof. All such singlestereoisomers, mixtures and racemates are intended to be encompassedwithin the broad scope of the present invention. Compounds identifiedherein as single stereoisomers are meant to describe compounds that arepresent in a form that are at least 90% enantiomerically pure. Where thestereochemistry of the chiral carbons present in the chemical structuresillustrated herein is not specified, the chemical structure is intendedto encompass compounds containing either stereoisomer of each chiralcenter present in the compound. Such compounds may be obtainedsynthetically, according to the procedures described herein usingoptically pure (enantiomerically pure) or substantially optically purematerials. Alternatively, these compounds may be obtained byresolution/separation of a mixture of stereoisomers, including racemicmixtures, using conventional procedures. Exemplary methods that may beuseful for the resolution/separation of mixtures of stereoisomersinclude chromatography and crystallization/re-crystallization. Otheruseful methods may be found in “Enantiomers, Racemates, andResolutions,” J. Jacques et al., 1981, John Wiley and Sons, New York,N.Y., the disclosure of which is incorporated herein by reference.

In one embodiment of this invention, the group X—(CR¹R²)_(p)— is locatedon the

moiety in a position that is meta or para to the —Y—(CR⁴R⁵)_(n)— moiety.Preferably, the group X—(CR¹R²)_(p)— is located in a position that ismeta to the —Y—(CR⁴R⁵)_(n)— moiety.

In another embodiment, this invention is directed to a compound ofFormula II:

wherein:

X is selected from C₁-C₈ alkyl, halo, —OR¹⁰, —NR¹⁴R¹⁵, cyano, —COR¹³,COOR¹⁰, —OCOR¹³, —N(R¹⁷)COR¹³, —N(R¹⁷)CONR¹⁴R¹⁵, —N(R¹⁷)COOR¹³,—SO₂NR¹⁴R¹⁵, —C(═NR¹⁷)NR¹⁴R¹⁵, —N(R¹⁷)SO₂R¹⁶, and a 5 or 6-memberedheterocyclic group;

or X and an adjacent R³, taken together with the atoms to which they arebonded, form an alkylenedioxy moiety;

Z is CH or N, wherein k is 0, 1 or 2;

Y is —O— or —C(R⁴)(R⁵)—;

W¹ is C₃-C₈ cycloalkyl, aryl or Het, wherein said C₃-C₈ cycloalkyl, Arand Het are optionally unsubstituted or substituted with one or moregroups independently selected from halo, cyano, nitro, C₁-C₆ alkyl,C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₄ alkyl-CO₂R¹⁰, —C₀-C₄ alkyl-C(O)SR,—C₀-C₄ alkyl-CONR¹¹R¹², —C₀-C₄ alkyl-COR¹³, —C₀-C₄ alkyl-NR¹¹R¹², —C₀-C₄alkyl-SR¹⁰, —C₀-C₄ alkyl-OR¹⁰, —C₀-C₄ alkyl-SO₃H, —C₀-C₄alkyl-SO₂NR¹¹R¹², —C₀-C₄ alkyl-SO₂R¹⁰, —C₀-C₄ alkyl-SOR¹³, —C₀-C₄alkyl-OCOR¹³, —C₀-C₄ alkyl-OC(O)NR¹¹R¹², —C₀-C₄ alkyl-OC(O)OR¹³, —C₁-C₄alkyl-NR¹¹C(O)OR¹³, —C₀-C₄ alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₄alkyl-NR¹¹COR¹³, where said C₀-C₆ alkyl is optionally unsubstituted orsubstituted by one or more halo substituents;

W² is selected from H, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,—C₀-C₄ alkyl-NR¹¹R¹², —C₀-C₄ alkyl-SR¹⁰, —C₀-C₄ alkyl-OR¹⁰, —C₀-C₄alkyl-CO₂R¹⁰, —C₀-C₄ alkyl-C(O)SR¹⁰, —C₀-C₄ alkyl-CONR¹¹R¹², —C₀-C₄alkyl-COR¹³, —C₀-C₄ alkyl-OCOR¹³, —C₀-C₄ alkyl-OCONR¹¹R¹², —C₀-C₄alkyl-NR¹¹CONR¹¹R¹², —C₀-C₄ alkyl-NR¹¹CORR¹³, —C₀-C₄ alkyl-Het, —C₀-C₄alkyl-Ar and —C₀-C₄ alkyl-C₃-C₇ cycloalkyl, wherein said C₁-C₆ alkyl isoptionally unsubstituted or substituted by one or more halosubstituents, and wherein the C₃-C₇ cycloalkyl, Ar and Het moieties ofsaid —C₀-C₄ alkyl-Het, —C₀-C₄ alkyl-Ar and —C₀-C₄ alkyl-C₃-C₇ cycloalkylare optionally unsubstituted or substituted with one or more groupsindependently selected from halo, cyano, nitro, C₁-C₆ alkyl, C₃-C₆alkenyl, C₃-C₆ alkynyl, —C₀-C₄ alkyl-CO₂R¹⁰, —C₀-C₄ alkyl-C(O)SR¹⁰,—C₀-C₄ alkyl-CONR¹¹R¹², —C₀-C₄ alkyl-COR¹³, —C₀-C₄ alkyl-NR¹¹R¹², —C₀-C₄alkyl-SR¹⁰, —C₀-C₄ alkyl-OR¹⁰, —C₀-C₄ alkyl-SO₃H, —C₀-C₄alkyl-SO₂NR¹¹R¹², —C₀-C₄ alkyl-SO₂R¹⁰, —C₀-C₄ alkyl-SOR¹³, —C₀-C₄alkyl-OCOR¹³, —C₀-C₄ alkyl-OC(O)NR¹¹R¹², —C₀-C₄ alkyl-OC(O)OR¹³, —C₀-C₄alkyl-NR¹¹C(O)OR¹³, —C₀-C₄ alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₄alkyl-NR¹¹COR¹³, where said C₁-C₆ alkyl is optionally unsubstituted orsubstituted by one or more halo substituents;

W³ is selected from the group consisting of: H, halo, C₁-C₆ alkyl,—C₀-C₄ alkyl-NR¹¹R¹², —C₀-C₄ alkyl-SR¹⁰, —C₀-C₄ alkyl-OR¹⁰, —C₀-C₄alkyl-CO₂R¹⁰, —C₀-C₄ alkyl-C(O)SR¹⁰, —C₁-C₄ alkyl-CONR¹¹ R¹², —C₀-C₄alkyl-COR¹³, —C₀-C₄ alkyl-OCOR¹³, —C₀-C₄ alkyl-OCONR¹¹R¹², —C₀-C₄alkyl-NR¹¹CONR¹¹R¹², —C₀-C₄ alkyl-NR¹¹COR¹³, —C₀-C₄ alkyl-Het, —C₁-C₄alkyl-Ar and —C₁-C₄ alkyl-C₃-C₇ cycloalkyl, wherein said C₁-C₆ alkyl isoptionally unsubstituted or substituted by one or more halosubstituents;

Q is Ar or Het; wherein said Ar and Het are optionally unsubstituted orsubstituted with one or more groups independently selected from halo,cyano, nitro, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₄alkyl-CO₂R¹⁰, —C₀-C₄ alkyl-C(O)SR¹⁰, —C₀-C₄ alkyl-CONR¹¹R¹², —C₀-C₄alkyl-COR¹³, —C₀-C₄alkyl-NR¹¹R¹², —C₀-C₄ alkyl-SR¹⁰, —C₀-C₄ alkyl-OR¹⁰,—C₀-C₄ alkyl-SO₃H, —C₀-C₄ alkyl-SO₂NR¹¹R¹², —C₀-C₄ alkyl-SO₂R¹⁰, —C₀-C₄alkyl-SOR¹³, —C₀-C₄ alkyl-OCOR¹³, —C₀-C₄alkyl-OC(O)NR¹¹R¹², —C₀-C₄alkyl-OC(O)OR¹³, —C₀-C₄ alkyl-NR¹¹C(O)OR¹³, —C₀-C₄alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₄ alkyl-NR¹¹COR¹³, where said C₁-C₆alkyl is optionally unsubstituted or substituted by one or more halosubstituents,

p is 0-4;

n is 3;

m is 0 or 1;

q is 0 or 1;

t is 0;

each R¹ and R² are independently selected from H, fluoro, C₁-C₆ alkyl,—C₀-C₄ alkyl-OR¹⁰, —C₀-C₄ alkyl-SR¹⁰, —C₁-C₄ alkyl-Het, —C₁-C₄ alkyl-Arand —C₁-C₄ alkyl-C₃-C₇ cycloalkyl, where said C₁-C₆ alkyl or any of saidC₁-C₄ alkyl is optionally unsubstituted or substituted by one or morehalo substituents;

or R¹ and R² together with the carbon to which they are attached form a3-5 membered carbocyclic or heterocyclic ring, wherein said heterocyclicring contains one, or more heteroatoms selected from N, O and S, whereany of said C₁-C₆ alkyl is optionally unsubstituted or substituted byone or more halo substituents;

each R³ is the same or different and is independently selected fromhalo, cyano, C₁-C₆ alkyl, —C₀-C₄ alkyl-NR¹¹R¹², —C₀-C₄ alkyl-OR¹⁰,—C₀-C₄ alkyl-SO₂NR¹¹R¹², and —C₀-C₄ alkyl-CO₂H, wherein said C₁-C₆ alkylis optionally unsubstituted or substituted by one or more halosubstituents;

each R⁴ and R⁵ is independently selected from H, fluoro and C₁-C₆ alkyl;

R⁶ and R⁷ are each independently selected from H, fluoro and C₁-C₆alkyl;

R⁸ and R⁹ are each independently selected from H, fluoro and C₁-C₆alkyl;

R¹⁰ is selected from H, C₁-C₆ alkyl, —C₀-C₄ alkyl-Ar, —C₀-C₄ alkyl-Hetand —C₀-C₄ alkyl-C₃-C₇ cycloalkyl;

each R¹¹ and each R¹² are independently selected from H, C₁-C₆ alkyl,—C₀-C₄ alkyl-Ar, —C₀-C₄ alkyl-Het and —C₀-C₄ alkyl-C₃-C₇ cycloalkyl, orR¹¹ and R¹² together with the nitrogen to which they are attached form a4-7 membered heterocyclic ring which optionally contains one or moreadditional heteroatoms selected from N, O, and S;

R¹³ is selected from C₁-C₆ alkyl, —C₀-C₄ alkyl-Ar, —C₀-C₄ alkyl-Het and—C₀-C₄ alkyl-C₃-C₇ cycloalkyl;

R¹⁴ and R¹⁵ are each independently selected from H, C₁-C₆ alkyl, C₃-C₆alkenyl, C₃-C₆ alkynyl, —C₀-C₄ alkyl-Ar, —C₀-C₄ alkyl-Het, —C₀-C₄alkyl-C₃-C₇ cycloalkyl, —C₀-C₄ alkyl-O—Ar, —C₀-C₄ alkyl-O-Het, —C₀-C₄alkyl-O—C₃-C₇ cycloalkyl, —C₀-C₄ alkyl-S(O)_(x)—C₁-C₄ alkyl, —C₀-C₄alkyl-S(O)_(x)—Ar, —C₀-C₄ alkyl-S(O)_(x)-Het, —C₀-C₄alkyl-S(O)_(x)—C₃-C₇ cycloalkyl, —C₀-C₄ alkyl-NH—Ar, —C₀-C₄alkyl-NH-Het, —C₀-C₄ alkyl-NH—C₃-C₇ cycloalkyl, —C₀-C₄ alkyl-N(C₁-C₄alkyl)-Ar, —C₀-C₄ alkyl-N(C₁-C₄ alkyl)-Het, —C₀-C₄ alkyl-N(C₁-C₄alkyl)C₃-C₇ cycloalkyl, —C₀-C₄ alkyl-Ar, —C₀-C₄ alkyl-Het and —C₀-C₄alkyl-C₃-C₇ cycloalkyl, where x is 0, 1 or 2, or R¹⁴ and R₁₆, togetherwith the nitrogen to which they are attached, form a 4-7 memberedheterocyclic ring which optionally contains one or more additionalheteroatoms selected from N, O, and S, wherein said C₁-C₆ alkyl, C₃-C₆alkenyl, C₃-C₆ alkynyl are optionally substituted by one or more of thesubstituents independently selected from the group halo, —OH, —SH, —NH₂,—NH(unsubstituted C₁-C₄ alkyl), —N(unsubstituted C₁-C₄alkyl)(unsubstituted C₁-C₄ alkyl), unsubstituted —OC₁-C₄ alkyl, —CO₂H,—CO₂(unsubstituted C₁-C₄ alkyl), —CONH₂, —CONH(unsubstituted C₁-C₄alkyl), —CON(unsubstituted C₁-C₄ alkyl)(unsubstituted C₁-C₄ alkyl),—SO₃H, —SO₂NH₂, —SO₂NH(unsubstituted C₁-C₄ alkyl) and—SO₂N(unsubstituted C₁-C₄ alkyl)(unsubstituted C₁-C₄ alkyl);

R¹⁶ is C₁-C₆ alkyl, —C₀-C₄ alkyl-Ar or —C₀-C₄ alkyl-Het; and

R¹⁷ is H, C₁-C₆ alkyl, —C₀-C₄ alkyl-Ar or —C₀-C₄ alkyl-Het;

provided that X is not COOR¹⁰ when Y is —O—, p is 0-4, n is 3, m is 1, qis 0 or 1, t is 0, each R¹ and R² is independently selected from H,C₁-C₆ alkyl, —OH, —O—C₁-C₆ alkyl, —SH, and —S—C₁-C₆ alkyl, each R⁴, R⁵,R⁶, R⁷, R⁸ and R⁹ are independently H or C₁-C₄ alkyl, k is 0 or 1, W³ isH, W¹ and w² are each independently selected from C₃-C₈ cycloalkyl andaryl and R³ and Q are as defined above; or

provided that the compound is not:

-   5-[3-[[(3,4-dichlorophenyl)methyl][2-(2-naphthalenyl)ethyl]amino]propoxy]-3-methoxy-1,2-benzenedicarboxylic    acid, or-   5-[3-[[(3,4-dichlorophenyl)methyl][2-(2-naphthalenyl)ethyl]amino]propoxy]-3-methoxy-1,2-benzenedicarboxylic    acid, dimethyl ester;

or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, this invention is directed to methods for theprevention or treatment of an LXR mediated disease or conditioncomprising administering a therapeutically effective amount of acompound having Formula II-A:

wherein:

X is selected from C₁-C₈ alkyl, halo, —OR¹⁰, —NR¹⁴R¹⁵, cyano, —COR¹³,COOR¹⁰, —OCOR¹³, —N(R¹⁷)COR¹³, —N(R¹⁷)CONR¹⁴R¹⁵, —N(R¹⁷)COOR¹³,—SO₂NR¹⁴R¹⁵, —C(═NR¹⁷)NR¹⁴R¹⁵, —N(R¹⁷)SO₂R¹⁶, and a 5 or 6-memberedheterocyclic group;

or X and an adjacent R³, taken together with the atoms to which they arebonded, form an alkylenedioxy moiety;

Z is CH or N, wherein k is 0, 1 or 2;

Y is —O— or —C(R⁴)(R⁵)—;

W¹ is C₃-C₈ cycloalkyl, aryl or Het, wherein said C₃-C₈ cycloalkyl, Arand Het are optionally unsubstituted or substituted with one or moregroups independently selected from halo, cyano, nitro, C₁-C₆ alkyl,C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₄ alkyl-CO₂R¹⁰, —C₀-C₄alkyl-C(O)SR¹°, —C₀-C₄ alkyl-CONR¹¹R¹², —C₀-C₄ alkyl-COR¹³, —C₀-C₄alkyl-NR¹¹R¹², —C₀-C₄ alkyl-SR¹⁰, —C₀-C₄ alkyl-OR¹⁰, —C₀-C₄ alkyl-SO₃H,—C₀-C₄ alkyl-SO₂NR¹¹R¹², —C₀-C₄ alkyl-SO₂R¹⁰, —C₀-C₄ alkyl-SOR¹³, —C₀-C₄alkyl-OCOR¹³, —C₀-C₄ alkyl-OC(O)NR¹¹R¹², —C₀-C₄ alkyl-OC(O)OR¹³, —C₀-C₄alkyl-NR¹¹C(O)OR¹³, —C₀-C₄ alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₄alkyl-NR¹¹CR¹³, where said C₁-C₆ alkyl is optionally unsubstituted orsubstituted by one or more halo substituents;

W² is selected from H, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,—C₀-C₄ alkyl-NR¹¹R¹², —C₀-C₄ alkyl-SR¹⁰, —C₀-C₄ alkyl-OR¹⁰, —C₀-C₄alkyl-CO₂R¹⁰, —C₀-C₄ alkyl-C(O)SR¹⁰, —C₀-C₄ alkyl-CONR¹¹R¹², —C₀-C₄alkyl-COR¹³, —C₀-C₄ alkyl-OCOR¹³, —C₀-C₄ alkyl-OCONR¹¹R¹², —C₀-C₄alkyl-NR¹¹CONR¹¹R¹², —C₀-C₄ alkyl-NR¹¹COR¹³, —C₀-C₄ alkyl-Het, —C₀-C₄alkyl-Ar and —C₀-C₄ alkyl-C₃-C₇ cycloalkyl, wherein said C₁-C₆ alkyl isoptionally unsubstituted or substituted by one or more halosubstituents, and wherein the C₃-C₇ cycloalkyl, Ar and Het moieties ofsaid —C₀-C₄ alkyl-Het, —C₀-C₄ alkyl-Ar and —C₀-C₄ alkyl-C₃-C₇ cycloalkylare optionally unsubstituted or substituted with one or more groupsindependently selected from halo, cyano, nitro, C₁-C₆ alkyl, C₃-C₆alkenyl, C₃-C₆ alkynyl, —C₀-C₄ alkyl-CO₂R¹⁰, —C₀-C₄ alkyl-C(O)SR¹⁰,—C₀-C₄ alkyl-CONR¹¹R¹², —C₀-C₄ alkyl-COR¹³, —C₀-C₄ alkyl-NR¹¹R¹², —C₀-C₄alkyl-SR¹⁰, —C₀-C₄ alkyl-OR¹⁰, —C₀-C₄ alkyl-SO₃H, —C₀-C₄alkyl-SO₂NR¹¹R¹², —C₀-C₄ alkyl-SO₂R¹⁰, —C₀-C₄ alkyl-SOR¹³, —C₀-C₄alkyl-OCOR¹³, —C₀-C₄ alkyl-OC(O)NR¹¹R¹², —C₀-C₄ alkyl-OC(O)OR¹³, —C₀-C₄alkyl-NR¹¹C(O)OR¹³, —C₀-C₄ alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₄alkyl-NR¹¹COR¹³, where said C₁-C₆ alkyl is optionally unsubstituted orsubstituted by one or more halo substituents;

W³ is selected from the group consisting of H, halo, C₁-C₆ alkyl, —C₀-C₄alkyl-NR¹¹R¹², —C₀-C₄ alkyl-SR¹⁰, —C₀-C₄ alkyl-OR¹⁰, —C₀-C₄alkyl-CO₂R¹⁰, —C₀-C₄ alkyl-C(O)SR¹⁰, —C₀-C₄ alkyl-CONR¹¹R¹², —C₀-C₄alkyl-COR¹³, —C₀-C₄ alkyl-OCOR¹³, —C₀-C₄ alkyl-OCONR¹¹R¹², —C₀-C₄alkyl-NR¹¹CONR¹¹R¹², —C₀-C₄ alkyl-NR¹¹COR¹³, —C₀-C₄ alkyl-Het, —C₁-C₄alkyl-Ar and —C₁-C₄ alkyl-C₃-C₇ cycloalkyl, wherein said C₁-C₆ alkyl isoptionally unsubstituted or substituted by one or more halosubstituents;

Q is Ar or Het; wherein said Ar and Het are optionally unsubstituted orsubstituted with one or more groups independently selected from halo,cyano, nitro, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₄alkyl-CO₂R¹⁰, —C₀-C₄ alkyl-C(O)SR¹⁰, —C₀-C₄ alkyl-CONR¹¹R¹², —C₀-C₄alkyl-COR¹³, —C₀-C₄alkyl-NR¹¹R¹², —C₀-C₄ alkyl-SR¹⁰, —C₀-C₄ alkyl-OR¹⁰,—C₀-C₄ alkyl-SO₃H, —C₀-C₄ alkyl-SO₂NR¹¹R¹², —C₀-C₄alkyl-SO₂R¹⁰, —C₀-C₄alkyl-SOR¹³, —C₀-C₄ alkyl-OCOR¹³, —C₀-C₄ alkyl-OC(O)NR¹¹R¹², —C₀-C₄alkyl-OC(O)OR¹³, —C₀-C₄ alkyl-NR¹¹C(O)OR¹³, —C₀-C₄alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₄ alkyl-NR¹¹COR¹³, where said C₁-C₆alkyl is optionally unsubstituted or substituted by one or more halosubstituents,

p is 0-4;

n is 3;

m is 0 or 1;

q is 0 or 1;

t is 0;

each R¹ and R² are independently selected from H, fluoro, C₁-C₆ alkyl,—C₀-C₄ alkyl-OR¹⁰, —C₀-C₄ alkyl-SR¹⁰, —C₁-C₄ alkyl-Het, —C₁-C₄ alkyl-Arand —C₁-C₄ alkyl-C₃-C₇ cycloalkyl, where said C₁-C₆ alkyl or any of saidC₁-C₄ alkyl is optionally unsubstituted or substituted by one or morehalo substituents;

or R¹ and R² together with the carbon to which they are attached form a3-5 membered carbocyclic or heterocyclic ring, wherein said heterocyclicring contains one, or more heteroatoms selected from N, O, and S, whereany of said C₁-C₆ alkyl is optionally unsubstituted or substituted byone or more halo substituents;

each R³ is the same or different and is independently selected fromhalo, cyano, C₁-C₆alkyl, —C₀-C₄ alkyl-NR¹¹R¹², —C₀-C₄ alkyl-OR¹⁰, —C₀-C₄alkyl-SO₂NR¹¹R¹², and —C₀-C₄ alkyl-CO₂H, wherein said C₁-C₆ alkyl isoptionally unsubstituted or substituted by one or more halosubstituents;

each R⁴ and R⁵ is independently selected from H, fluoro and C₁-C₆ alkyl;

R⁶ and R⁷ are each independently selected from H, fluoro and C₁-C₆alkyl;

R⁸ and R⁹ are each independently selected from H, fluoro and C₁-C₆alkyl;

R¹⁰ is selected from H, C₁-C₆ alkyl, —C₀-C₄ alkyl-Ar, —C₀-C₄ alkyl-Hetand —C₀-C₄ alkyl-C₃-C₇ cycloalkyl;

each R¹¹ and each R¹² are independently selected from H, C₁-C₆ alkyl,—C₀-C₄ alkyl-Ar, —C₀-C₄ alkyl-Het and —C₀-C₄ alkyl-C₃-C₇ cycloalkyl, orR¹¹ and R¹² together with the nitrogen to which they are attached form a4-7 membered heterocyclic ring which optionally contains one or moreadditional heteroatoms selected from N, O, and S;

R¹³ is selected from C₁-C₆ alkyl, —C₀-C₄ alkyl-Ar, —C₀-C₄ alkyl-Het and—C₀-C₄ alkyl-C₃-C₇ cycloalkyl;

R¹⁴ and R¹⁵ are each independently selected from H, C₁-C₆ alkyl, C₃-C₆alkenyl, C₃-C₆alkynyl, —C₀-C₄ alkyl-Ar, —C₀-C₄ alkyl-Het, —C₀-C₄alkyl-C₃-C₇ cycloalkyl, —C₀-C₄ alkyl-O—Ar, —C₀-C₄ alkyl-O-Het, —C₀-C₄alkyl-O—C₃-C₇ cycloalkyl, —C₀-C₄ alkyl-S(O)_(x)—C₁-C₄ alkyl, —C₀-C₄alkyl-S(O)_(x), Ar, —C₀-C₄ alkyl-S(O)_(x), Het, —C₀-C₄alkyl-S(O)_(x)—C₃-C₇ cycloalkyl, —C₀-C₄ alkyl-NH—Ar, —C₀-C₄alkyl-NH-Het, —C₀-C₄ alkyl-NH—C₃-C₇ cycloalkyl, —C₀-C₄ alkyl-N(C₁-C₄alkyl)-Ar, —C₀-C₄ alkyl-N(C₁-C₄ alkyl)-Het, —C₀-C₄ alkyl-N(C₁-C₄alkyl)-C₃-C₇ cycloalkyl, —C₀-C₄ alkyl-Ar, —C₀-C₄ alkyl-Het and —C₀-C₄alkyl-C₃-C₇ cycloalkyl, where x is 0, 1 or 2, or R¹⁴ and R¹⁵, togetherwith the nitrogen to which they are attached, form a 4-7 memberedheterocyclic ring which optionally contains one or more additionalheteroatoms selected from N, O, and S, wherein said C₁-C₆ alkyl, C₃-C₆alkenyl, C₃-C₆ alkynyl are optionally substituted by one or more of thesubstituents independently selected from the group halo, —OH, —SH, —NH₂,—NH(unsubstituted C₁-C₄ alkyl), —N(unsubstituted C₁-C₄alkyl)(unsubstituted C₁-C₄ alkyl), unsubstituted —OC₁-C₄ alkyl, —CO₂H,—CO₂(unsubstituted C₁-C₄ alkyl), —CONH₂, —CONH(unsubstituted C₁-C₄alkyl), —CON(unsubstituted C₁-C₄ alkyl)(unsubstituted C₁-C₄ alkyl),—SO₃H, —SO₂NH₂, —SO₂NH(unsubstituted C₁-C₄ alkyl) and—SO₂N(unsubstituted C₁-C₄ alkyl)(unsubstituted C₁-C₄ alkyl);

R¹⁶ is C₁-C₆ alkyl, —C₀-C₄ alkyl-Ar or —C₀-C₄ alkyl-Het; and

R¹⁷ is H, C₁-C₆ alkyl, —C₀-C₄ alkyl-Ar or —C₀-C₄ alkyl-Het;

provided that X is not COOR¹⁰ when Y is —O—, p is 0-4, n is 3, m is 1, qis 0 or 1, t is 0, each R¹ and R² is independently selected from H,C₁-C₆ alkyl, —OH, —O—C₁-C₆ alkyl, —SH, and —S—C₁-C₆ alkyl, each R⁴, R⁵,R⁶, R⁷, R⁸ and R⁹ are independently H or C₁-C₄ alkyl, k is 0 or 1, W³ isH, W¹ and W² are each independently selected from C₃-C₈ cycloalkyl andaryl and R³ and Q are as defined above;

or a pharmaceutically acceptable salt or solvate thereof.

Unless otherwise provided, each alkyl, alkoxy, alkenyl, alkynyl,cycloalkyl, aryl or Het herein is independently unsubstituted orsubstituted with one ore more substituents defined hereinabove.

The LXR modulating agents of this invention may contain the variety of Xgroups defined above. In more specific embodiments of this invention, Xis selected from C₁-C₆ alkyl, halo, —OR¹⁰, —NR¹⁴R¹⁵, cyano, —COR¹³,—COOR¹⁰, OCOR¹³, —N(R¹⁷)CONR¹⁴R¹⁵, —N(R¹⁷)COR¹³, —SO₂NR¹⁴R¹⁵,—N(R¹⁷)SO₂R¹⁶, and a 5 or 6-membered heterocyclic group or X and anadjacent R³, taken together with the atoms to which they are bonded,form an alkylenedioxy moiety, where R¹⁰ is H, C₁-C₄ alkyl or phenyl; R¹³is H, C₁-C₄ alkyl, —C₀-C₄ alkyl-C₃-C₇ cycloalkyl, or —C₀-C₄alkyl-phenyl; R¹⁴ and R¹⁵ are each independently selected from H, C₁-C₆alkyl, —C₀-C₄ alkyl-Ar, —C₀-C₄ alkyl-Het, —C₀-C₄ alkyl-C₃-C₇ cycloalkyl,—C₀-C₄ alkyl-O—Ar, —C₀-C₄ alkyl-O-Het, —C₀-C₄ alkyl-O—C₃-C₇ cycloalkyl,—C₀-C₄ alkyl-S(O)₂-C₁-C₄ alkyl, —C₀-C₄ alkyl-S(O)₂—Ar, —C₀-C₄alkyl-S(O)₂-Het, —C₀-C₄ alkyl-S(O)₂-C₃-C₇ cycloalkyl, —C₀-C₄alkyl-NH—Ar, —C₀-C₄ alkyl-NH-Het, —C₀-C₄ alkyl-NH—C₃-C₇ cycloalkyl,—C₀-C₄ alkyl-N(C₁-C₄ alkyl)-Ar, —C₀-C₄ alkyl-N(C₁-C₄ alkyl)-Het, —C₀-C₄alkyl-N(C₁-C₄ alkyl)-C₃-C₇ cycloalkyl, —C₀-C₄ alkyl-Ar, —C₀-C₄ alkyl-Hetand —C₀-C₄ alkyl-C₃-C₇ cycloalkyl, or R¹⁴ and R¹⁵, together with thenitrogen to which they are attached, form a 4-7 membered heterocyclicring which optionally contains one or more additional heteroatomsselected from N, O, and S, wherein said C₁-C₆ alkyl is optionallysubstituted by one or more of the substituents independently selectedfrom the group halo, —OH, —SH, —NH₂, —NH(unsubstituted C₁-C₄ alkyl),—N(unsubstituted C₁-C₄ alkyl)(unsubstituted C₁-C₄ alkyl), unsubstituted—OC₁-C₄ alkyl, —CO₂H, —CO₂(unsubstituted C₁-C₄ alkyl), —CONH₂,—CONH(unsubstituted C₁-C₄ alkyl), —CON(unsubstituted C₁-C₄alkyl)(unsubstituted C₁-C₄ alkyl), —SO₃H, —SO₂NH₂, —SO₂NH(unsubstitutedC₁-C₄ alkyl) and —SO₂N(unsubstituted C₁-C₄ alkyl)(unsubstituted C₁-C₄alkyl); R¹⁶ is C₁-C₄ alkyl or phenyl; and R¹⁷ is H or C₁-C₄ alkyl.

More specifically, X and an adjacent R³, taken together with the phenylring to which they are bound form a benzo [1,3]dioxyl group. In otherspecific embodiments, X is chloro, bromo, cyano, carboxy-,methylcarboxy-, hydroxy, methoxy, methyl, trifluoromethyl,1,3-dihydroxy-prop-2-yl (—CH(CH₂OH)₂, isopropyl, n-butyl, isobutyl,2,2-dimethylpropyl, phenylcarbonyl, triazolyl, tetrazolyl, —NH₂, —NHCH₃,—NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH₂CH₂CH₂CH₃, —NHCH₂CH₂CH₂CH₂CH₂CH₃,—NHCH₂C(CH₃)₃, —NHCH₂CH(CH₃)₂, —NHCH₂CH₂CH(CH₃)₂, —NH-cyclopentyl,—NH-phenyl, —NHCH₂-cyclopropyl, —NHCH(CH₃)₂, —NHCH₂CF₃, —N(CH₃)₂,—N(CH₂CH₃)₂, —NHCH(CH₂CH₃)₂, —NHCH₂CH(CH₂CH₃)₂, —NHCH₂CH₂OH, —NHCH₂CO₂H,—N(CH₃)CH₂CO₂H, —NHC(CH₃)₂CO₂H, —NHCH(CH₃)CO₂H, —(R)—NHCH(CH₃)CO₂H,—(S)—NHCH(CH₃)CO₂H, —NHCH₂-1H-imidazol-2-yl,—NHCH₂-(1-CH₃-imidazol-2-yl, —NH-(pyrimidin-2-yl), -morpholin-4-yl,-thiomorpholin-4-yl, -piperidin-1-yl, -piperidin-1-yl-(4-carboxylicacid), -piperidin-1-yl-(4-acetic acid), -piperidin-4-yl-(1-acetic acid),-2,5-dimethyl-pyrrol-1-yl, -pyrrolidin-1-yl,—((R)-2-CO₂H-pyrrolidin-1-yl), —((S)-2-CO₂H-pyrrolidin-1-yl),-piperazin-1-yl, -(4-methyl-piperazin-1-yl), -piperazin-1-yl-(4-aceticacid), —NHCH₂-(5-bromo-thien-2-yl), —NHCH₂-1H-imidazol-2-yl,—NHCH₂-(1-methyl-imidazol-2-yl, —NHCOCH₃, —N(CH₃)COCH₃, —NHCO₂C(CH₃)₃,—NHCOCH₂CH₃, —NHCOC(CH₃)₂, —NHCO-furan-2-yl, —N(CH₃)CO-furan-2-yl,—NHCO-thien-2-yl, —NHCO-cyclopropyl, —NHCO-(5-bromo-thien-2-yl,—NHCO-(2,5-dimethyl-pyrrol-3-yl), —NHSO₂CH₃, —N(CH₃)SO₂CH₃, —NHSO₂CF₃,—NHSO₂phenyl, —N(CH₃)SO₂phenyl, —NHSO₂CH₂CH₃, —NHSO₂CH₂CF₃,—NHSO₂CH₂CH₂CH₃, —NHSO₂CH(CH₃)₂, —NHCONH(2-chlorophenyl),—N(CH₃)CONH(3,5-dimethoxyphenyl), —N(CH₃)CONH(2-chlorophenyl),—N(CH₃)CO-(benzo[1,3]diox-5-yl), —SO₂NHCH₃, and —SO₂N(CH₃)₂.

It will be understood by those skilled in the art, that the triazolyl ortetrazolyl groups present in the compounds of this invention will existin different tautomeric forms, as follows (where R is H or asubstituent, such as a protecting group):

As a convention, compounds exemplified herein have been depicted andhave been assigned names based on the structure of Tautomeric Form A(above) for each of the triazolyl and tetrazolyl groups. It is to beunderstood that any reference to such tautomeric compounds is intendedto encompass all tautomers and any mixtures of tautomers thereof, andshould not be interpreted to limit the scope of the compounds of thisinvention or of the intermediates used in the preparation thereof.

In specific embodiments, the compounds of this invention of thisinvention are defined wherein p is 0-3. In specific embodiments, p is 0,1 or 2.

In other embodiments, each R¹ and R² are independently H or C₁-C₄ alkylor R¹ and R² together with the carbon to which they are attached form a3-5 membered carbocyclic ring. By virtue of the definitions given abovefor the term “alkyl”, this definition of R¹ and R² also encompassesalkyl and cycloalkyl groups that are optionally substituted with thesubstituents specified in the definitions above. In specific embodimentsof the compounds of this invention, R¹ and R² are independently selectedfrom H and C₁-C₄ alkyl, specifically methyl and hydroxymethyl-, or R¹and R² together with the carbon to which they are attached form aspiro-cyclopropyl, cyclobutyl or cyclopentyl ring.

The group

describes a 6-membered aromatic ring, specifically, a phenyl or pyridylring, which may be unsubstituted (k=0) or substituted by one or moresubstituents R³. In the specific embodiments of this invention, Z is CH(which includes C(R³)) or N. The total number of R³ substituents thatmay be present in a compound of this invention is represented by “k”.When Z is CR³, k is 0-4, meaning that there can be up to four R³substituents on the 6-membered aromatic ring. When Z is CH or N, k is0-3, meaning that there can be up to three R³ substituents on the6-membered aromatic ring. In this embodiment, R³ is not attached to theZ moiety (N or C atom) of the ring. In the embodiments of thisinvention, k is 0 or 1.

In the embodiments wherein k is 1 or more, each R³ may be the same ordifferent and may be independently selected from halo, C₁-C₄ alkyl andC₁-C₄ alkoxy. By virtue of the definitions given above for the term“alkyl”, this definition of R³ also encompasses alkyl groups that areoptionally substituted with the substituents specified in thedefinitions above. In the specific embodiments of this invention, R³ ismethyl, trifluoromethyl, chloro or methoxy.

In another embodiment of the compounds this invention, R⁴ and R⁵ areindependently selected from H and C₁-C₃ alkyl. By virtue of thedefinition given above for the term “alkyl”, R⁴ and R⁵ also encompassesthe alkyls optionally substituted with the substituents specified in thedefinition above. In specific embodiments of this invention, each R⁴ andR⁵ are H or one R⁴ or R⁵ is methyl.

When the moiety —Y(CR⁴R⁵)_(n)— is substituted and R⁴ and R⁵ aredifferent on at least one (CR⁴R⁵) moiety (e.g., when one of R⁴ or R⁵ ismethyl and the other of R⁴ and R⁵ is hydrogen) a chiral compound isobtained. Such chiral compounds preferably possess at least one R⁴ or R⁵substituent having the following stereochemistry (illustrated where Y is—O—):

where the substituent R⁴ is used merely to illustrate the stereochemicalorientation of a non-hydrogen substituent (e.g., methyl).

In another embodiment, the compounds of this invention are definedwherein n is 2-4. In specific embodiments, n is 3.

In the compounds of this invention, t may be 0 or 1. When Z is CH or CR³and t is 1, the compound of this invention is the N-oxide of thetertiary amine, having the formula:

When Z is CH, CR³ or N and t is 0, the compound of this invention is thetertiary amine having the formula:

In specific embodiments' of the compounds this invention, q is 1 and Reand R⁹ are both H.

Group Q is selected from C₃-C₇ cycloalkyl, aryl and Het. By virtue ofthe definitions given above for the terms “cycloalkyl”, “aryl” and“Het”, this definition of Q also encompasses cycloalkyl, aryl and Hetgroups that are optionally substituted from 1 to 4 times, morepreferably, from 1 to 3 times with the substituents specified in thedefinitions above. In one embodiment, Q is an aryl or Het group. Inspecific non-limiting embodiments, Q is a substituted or unsubstitutedphenyl or furanyl group or a benzo[1,3]dioxyl or benzo[1,4]dioxyl groupcontaining one, two or three substituents selected from halo, C₁-C₄alkyl; including C₁-C₄ haloalkyl, C₁-C₄ alkylthio; or —NR^(Q1)R^(Q2)where R^(Q1) and R^(Q2) taken together with the nitrogen to which theyare attached form a 4-7 membered heterocyclic ring, which may optionallycontain one or more additional heteroatoms selected form N, O and S.Specific substituents include fluoro, chloro, trifluoromethyl,tert-butyl, isopropyl, methylthio and piperidin-1-yl. More specifically,Q is 2-chloro-3-(trifluoromethyl)phenyl, 3-methyl-4-fluoro-phenyl,4-tert-butyl-phenyl, 4-(methylthio)phenyl, 2,4,5-trifluoro-phenyl,4-isopropyl-phenyl, 5-(piperidin-1-yl)-furan-2-yl, benzo[1,3]diox-5-yl,or 2,3-dihydrobenzo[1,4]dioxin-6-yl. In particular embodiments, Q is a2-chloro-3-(trifluoromethyl)phenyl group.

In one embodiment of the compounds of this invention, m is 0 or 1 and R⁶and R⁷ are independently selected from H and C₁-C₄ alkyl, specificallymethyl.

In yet another embodiment, W¹ is C₁-C₄ alkyl, aryl or Het; W² isselected from C₁-C₄ alkyl, C₂-C₄ alkynyl, —CO₂R¹⁰, —OR¹⁰, —NR¹¹R¹²,—CONR¹¹R¹², —OCOR¹³, —OCONR¹¹R¹², C₁-C₄ alkyl, —C₀-C₄ alkyl-OR¹⁰, —C₀-C₄alkyl-Het, —C₀-C₄ alkyl-Ar and —C₀-C₄ alkyl-C₃-C₆ cycloalkyl, and W³ isH or C₁-C₄ alkyl. By virtue of the definitions given above, for theterms “alkyl”, “cycloalkyl”, “aryl” and “Het”, W¹, W², and W³ alsoencompasses the foregoing groups optionally substituted with thesubstituents specified in the definitions above. In one embodiment, W¹and/or W² may be phenyl, naphthyl, thienyl, pyridyl, furanyl, pyrrolyl,cyclohexyl, cyclopentyl, morpholinyl, or pyrrolidinyl, where eachphenyl, naphthyl, thienyl, pyridyl, furanyl, pyrrolyl, cyclohexyl,cyclopentyl, morpholinyl, or pyrrolidinyl may be optionally substitutedfrom 1 to 3 times, more preferably from 1 to 2 times with one or more ofthe substituents defined hereinabove. For example, W¹ and/or W² may beindependently substituted by one or more substituents independentlyselected from C₁-C₄ alkyl, —OH, halo, —O—C₁-C₄ alkyl, and —C₁-C₄haloalkyl. In more specific embodiments, W¹ is selected from methyl,unsubstituted or substituted phenyl, naphthyl, pyridyl, thienyl orpyrrolyl. More specifically, W¹ is methyl, unsubstituted phenyl,naphthyl, pyridyl, thienyl or pyrrolyl or substituted phenyl or pyridylcontaining one or two substituents independently selected from halo,alkyl and alkoxy, specifically, chloro, methyl and methoxy. In specificembodiments, W¹ is methyl, phenyl, naphth-1-yl, pyrid-2-yl,4-methyl-pyrid-2-yl, thien-2-yl, thien-3-yl, pyrrol-2-yl,2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-methoxyphenyl, or4-methoxyphenyl. In other specific embodiments, W² is C₁-C₄ alkyl, C₂-C₄alkynyl, C₃-C₆ cycloalkyl, aryl, Het hydroxy, aryloxy-, C₁-C₄ alkoxy-,—OCOC₁-C₄ alkyl, —OCOaryl, or —NR^(W1)R^(W2), where R^(W1) and R^(W2)are independently H or C₁-C₄ alkyl or taken together with the nitrogento which they are attached form a 4-7 membered heterocyclic ring, whichmay optionally contain one or more additional heteroatoms selected formN, O and S. In more specific embodiments, W² is methyl, ethyl, ethynyl,isopropyl, n-butyl, 2-methylpropyl, trifluorormethyl, cyclohexyl,unsubstituted phenyl, hydroxy, methoxy, phenoxy, dimethylamino,morpholin-4-yl, phenylcarbonyloxy, or methylcarbonyloxy. In anotherembodiment, W³ is H or C₁-C₄ alkyl, specifically, methyl.

In other embodiments of this invention, the —C₀-C₆ alkyl- and —C₀-C₄alkyl- moieties of the substituents defined herein are unsubstituted—C₀-C₆ alkyl- and unsubstituted —C₀-C₄ alkyl- moieties, respectively.

It is to be understood that the present invention covers allcombinations of particular and preferred groups described hereinabove.

Specific embodiments of this invention comprise compounds wherein X isselected from C₁-C₆ alkyl, halo, —OR¹⁰, —NR¹⁴R¹⁵, cyano, —COR¹³,—COOR¹⁰, —OCOR¹³, —N(R¹⁷)CONR¹⁴R¹⁵, —N(R¹⁷)COR¹³, —SO₂NR¹⁴R¹⁵,—N(R¹⁷)SO₂R¹⁶, and a 5 or 6-membered heterocyclic group or X and anadjacent R³, taken together with the atoms to which they are bonded,form an alkylenedioxy moiety, where R¹⁰ is H, C₁-C₄ alkyl or phenyl, R¹³is H, C₁-C₄ alkyl, —C₀-C₄ alkyl-C₃-C₇ cycloalkyl, or —C₀-C₄alkyl-phenyl, R¹⁴ and R¹⁵ are each independently selected from H, C₁-C₆alkyl, —C₀-C₄ alkyl-Ar, —C₀-C₄ alkyl-Het, —C₀-C₄ alkyl-C₃-C₇ cycloalkyl,—C₀-C₄ alkyl-O—Ar, —C₀-C₄ alkyl-O-Het, —C₀-C₄ alkyl-O—C₃-C₇ cycloalkyl,—C₀-C₄ alkyl-S(O)₂-C₁-C₄ alkyl, —C₀-C₄ alkyl-S(O)₂—Ar, —C₀-C₄alkyl-S(O)₂-Het, —C₀-C₄ alkyl-S(O)₂-C₃-C₇ cycloalkyl, —C₀-C₄alkyl-NH—Ar, —C₀-C₄ alkyl-NH-Het, —C₀-C₄ alkyl-NH—C₃-C₇ cycloalkyl,—C₀-C₄ alkyl-N(C₁-C₄ alkyl)-Ar, —C₀-C₄ alkyl-N(C₁-C₄ alkyl)-Het, —C₀-C₄alkyl-N(C₁-C₄ alkyl)-C₃-C₇ cycloalkyl, —C₀-C₄ alkyl-Ar, —C₀-C₄ alkyl-Hetand —C₀-C₄ alkyl-C₃-C₇ cycloalkyl, or R¹⁴ and R¹⁵, together with thenitrogen to which they are attached, form a 4-7 membered heterocyclicring which optionally contains one or more additional heteroatomsselected from N, O, and S, wherein said C₁-C₆ alkyl is optionallysubstituted by one or more of the substituents independently selectedfrom the group halo, —OH, —SH, —NH₂, —NH(unsubstituted C₁-C₄ alkyl),—N(unsubstituted C₁-C₄ alkyl)(unsubstituted C₁-C₄ alkyl), unsubstituted—OC₁-C₄ alkyl, —CO₂H, —CO₂(unsubstituted C₁-C₄ alkyl), —CONH₂,—CONH(unsubstituted C₁-C₄ alkyl), —CON(unsubstituted C₁-C₄alkyl)(unsubstituted C₁-C₄ alkyl), —SO₃H, —SO₂NH₂, —SO₂NH(unsubstitutedC₁-C₄ alkyl) and —SO₂N(unsubstituted C₁-C₄ alkyl)(unsubstituted C₁-C₄alkyl), R¹⁶ is C₁-C₄ alkyl or phenyl, and R¹⁷ is H or C₁-C₄ alkyl; p is0, 1 or 2; R¹ and R² are independently H or C₁-C₄ alkyl or R¹ and R²together with the carbon to which they are attached form a 3-5 memberedcarbocyclic ring; k is 0 or k is 1 and R³ is halo, C₁-C₄ alkyl or C₁-C₄alkoxy; n is 3 and each R⁴ and R⁵ are independently selected from H andC₁-C₃ alkyl; Z is CH or N; Y is —O— or —C(R⁴)(R⁵)—; q is 1; R⁸ and R⁹are each H; Q is a substituted or unsubstituted phenyl or furanyl groupor a benzo[1,3]dioxyl or benzo[₁, 4]dioxyl group, where the substitutedphenyl or furanyl group contains one, two or three substituents selectedfrom halo, C₁-C₄ alkyl; C₁-C₄ alkylthio; or —NR^(Q1)R^(Q2), where R^(Q1)and R^(Q2) taken together with the nitrogen to which they are attachedform a 4-7 membered heterocyclic ring, which may optionally contain oneor more additional heteroatoms selected form N, O and S; t is 0 or 1; mis 0 or 1; R⁶ and R⁷ are independently selected from H and C₁-C₄ alkyl;W¹ is methyl, unsubstituted phenyl, naphthyl, pyridyl, thienyl orpyrrolyl or substituted phenyl or pyridyl containing one or twosubstituents independently selected from halo, alkyl and alkoxy,specifically, chloro, methyl and methoxy; W² is C₁-C₄ alkyl, C₂-C₄alkynyl, C₃-C₆ cycloalkyl, aryl, Het hydroxy, aryloxy-, C₁-C₄ alkoxy-,—OCOC₁-C₄ alkyl, —OCOaryl, or —NR^(W1)R^(W2), where R^(W1) and R^(W2)are independently H or C₁-C₄ alkyl or taken together with the nitrogento which they are attached form a 4-7 membered heterocyclic ring, whichmay optionally contain one or more additional heteroatoms selected formN, O and S; W³ is H or C₁-C₄ alkyl; or a pharmaceutically acceptablesalt or solvate thereof.

More specific embodiments of this invention comprise compounds wherein Xis chloro, bromo, cyano, carboxy-, methylcarboxy-, hydroxy, methoxy,methyl, trifluoromethyl, 1,3-dihydroxy-prop-2-yl (—CH(CH₂OH)₂,isopropyl, n-butyl, isobutyl, 2,2-dimethylpropyl, phenylcarbonyl,triazolyl, tetrazolyl, —NH₂, —NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃,—NHCH₂CH₂CH₂CH₃, —NHCH₂CH₂CH₂CH₂CH₂CH₃, —NHCH₂C(CH₃)₃, —NHCH₂CH(CH₃)₂,—NHCH₂CH₂CH(CH₃)₂, —NH-cyclopentyl, —NH-phenyl, —NHCH₂-cyclopropyl,—NHCH(CH₃)₂, —NHCH₂CF₃, —N(CH₃)₂, —N(CH₂CH₃)₂, —NHCH(CH₂CH₃)₂,—NHCH₂CH(CH₂CH₃)₂, —NHCH₂CH₂OH, —NHCH₂CO₂H, —N(CH₃)CH₂CO₂H,—NHC(CH₃)₂CO₂H, —NHCH(CH₃)CO₂H, —(R)—NHCH(CH₃)CO₂H, —(S)—NHCH(CH₃)CO₂H,—NHCH₂-1H-imidazol-2-yl, —NHCH₂-(1-CH₃-imidazol-2-yl,—NH-(pyrimidin-2-yl), -morpholin-4-yl, -thiomorpholin-4-yl,-piperidin-1-yl, -piperidin-1-yl-(4-carboxylic acid),-piperidin-1-yl-(4-acetic acid), -piperidin-4-yl-(1-acetic acid),-2,5-dimethyl-pyrrol-1-yl, -pyrrolidin-1-yl,—((R)-2-CO₂H-pyrrolidin-1-yl), —((S)-2-CO₂H-pyrrolidin-1-yl),-piperazin-1-yl, -(4-methyl-piperazin-1-yl), -piperazin-1-yl-(4-aceticacid), —NHCH₂-(5-bromo-thien-2-yl), —NHCH₂-1H-imidazol-2-yl,—NHCH2-(1-methyl-imidazol-2-yl, —NHCOCH₃, —N(CH₃)COCH₃, —NHCO₂C(CH₃)₃,—NHCOCH₂CH₃, —NHCOC(CH₃)₂, —NHCO-furan-2-yl, —N(CH₃)CO-furan-2-yl,—NHCO-thien-2-yl, —NHCO-cyclopropyl, —NHCO-(5-bromo-thien-2-yl,—NHCO-(2,5-dimethyl-pyrrol-3-yl), —NHSO₂CH₃, —N(CH₃)SO₂CH₃, —NHSO₂CF₃,—NHSO₂phenyl, —N(CH₃)SO₂phenyl, —NHSO₂CH₂CH₃, —NHSO₂CH₂CF₃,—NHSO₂CH₂CH₂CH₃, —NHSO₂CH(CH₃)₂, —NHCONH(2-chlorophenyl),—N(CH₃)CONH(3,5-dimethoxyphenyl), —N(CH₃)CONH(2-chlorophenyl),—N(CH₃)CO-(benzo[1,3]diox-5-yl), —SO₂NHCH₃, and —SO₂N(CH₃)₂; p is 0, 1or 2; R¹ and R² are H C₁-C₄ alkyl or R¹ and R² together with the carbonto which they are attached form a 3, 4 or 5 membered carbocyclic ring; Zis CH of N; k is 0 or k is 1 and R³ is methyl, trifluoromethyl, chloroor methoxy; n is 3 and R⁴ and R⁵ are independently selected from H andmethyl; Y is —O— or —C(R⁴)(R⁵)—; q is 1; R⁸ and R⁹ are each H; Q is2-chloro-3-(trifluoromethyl)phenyl, 3-methyl-4-fluoro-phenyl,4-tert-butyl-phenyl, 4-(methylthio)phenyl, 2,4,5-trifluoro-phenyl,4-isopropyl-phenyl, 5-(piperidin-1-yl)-furan-2-yl, benzo[1,3]diox-5-yl,or 2,3-dihydrobenzo[1,4]dioxin-6-yl; t is 0 or 1; m is 0 or 1; R⁶ and R⁷are independently selected from H and methyl; W¹ is methyl, phenyl,naphth-1-yl, pyrid-2-yl, 4-methyl-pyrid-2-yl, thien-2-yl, thien-3-yl,pyrrol-2-yl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,2-methoxyphenyl, or 4-methoxyphenyl; W² is methyl, ethyl, ethynyl,isopropyl, n-butyl, 2-methylpropyl, trifluorormethyl, cyclohexyl,unsubstituted phenyl, hydroxy, methoxy, phenoxy, dimethylamino,morpholin-4-yl, phenylcarbonyloxy, or methylcarbonyloxy; W³ is H ormethyl; or a pharmaceutically acceptable salt or solvate thereof.

Particular embodiments of this invention are directed to a compound ofFormula I, II, I-A or II-A, as defined above, wherein X is selected fromC₁-C₈ alkyl, halo, —OR¹⁰, —NR¹⁴R¹⁵, nitro, cyano, —COR¹³, —OCOR¹³,—N(R¹⁷)COR¹³, —N(R¹⁷)CONR¹⁴R¹⁵, —N(R¹⁷)COOR¹³, —SO₃H, —SO₂NR¹⁴R¹⁵,—C(═NR¹⁷)NR¹⁴R¹⁵, —N(R¹⁷)SO₂R¹⁶, and a 5 or 6-membered heterocyclicgroup; or X and an adjacent R³, taken together with the atoms to whichthey are bonded, form an alkylenedioxy moiety; Z is CH, CR³ or N,wherein when Z is CH or CR³, k is 0-4 and t is 0 or 1, and when Z is N,k is 0-3 and t is 0; Y is selected from —O—, —S—, —N(R¹⁰)—, and—C(R⁴)(R⁵)—; W¹ is selected from C₁-C₆ alkyl, C₃-C₈ cycloalkyl, aryl andHet, wherein said C₁-C₈ alkyl, C₃-C₈ cycloalkyl, Ar and Het areoptionally unsubstituted or substituted with one or more groupsindependently selected from halo, cyano, nitro, C₁-C₆ alkyl, C₃-C₆alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆ alkyl-C(O)SR¹⁰,—C₀-C₆ alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆ alkyl-NR¹¹R¹², —C₀-C₆alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-SO₃H, —C₀-C₆alkyl-SO₂NR¹¹R¹², —C₀-C₆ alkyl-SO₂R¹⁰, —C₀-C₆ alkyl-SOR¹³, —C₀-C₆alkyl-OCOR¹³, —C₀-C₆ alkyl-OC(O)NR¹¹R¹², —C₀-C₆ alkyl-OC(O)OR¹³, —C₀-C₆alkyl-NR¹¹C(O)OR¹³, —C₀-C₆ alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₆alkyl-NR¹¹COR¹³, where said C₁-C₆ alkyl, is optionally unsubstituted orsubstituted by one or more halo substituents; W² is selected from H,halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —C₀-C₆ alkyl-NR¹¹R¹²,—C₀-C₆ alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆alkyl-C(O)SR¹⁰, —C₀-C₆ alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆alkyl-COR¹³, —C₀-C₆ alkyl-OCONR¹¹R¹², —C₀-C₆ alkyl-NR¹¹CONR¹¹R¹², —C₀-C₆alkyl-NR¹¹COR¹³, —C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-Ar and —C₀-C₆alkyl-C₃-C₇ cycloalkyl, wherein said C₁-C₆ alkyl is optionallyunsubstituted or substituted by one or more halo substituents, andwherein the C₃-C₇ cycloalkyl, Ar and Het moieties of said —C₀-C₆alkyl-Het, —C₀-C₆ alkyl-Ar and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl areoptionally unsubstituted or substituted with one or more groupsindependently selected from halo, cyano, nitro, C₁-C₆ alkyl, C₃-C₆alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆ alkyl-C(O)SR¹⁰,—C₀-C₆ alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆ alkyl-NR¹¹R¹², —C₀-C₆alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-SO₃H, —C₀-C₆alkyl-SO₁₂NR¹¹R², —C₀-C₆ alkyl-SO₂R¹⁰, —C₀-C₆ alkyl-SOR¹³, —C₀-C₆alkyl-OCOR¹³, —C₀-C₆ alkyl-OC(O)NR¹¹R¹², —C₀-C₆ alkyl-OC(O)OR¹³, —C₀-C₆alkyl-NR¹¹C(O)OR¹³, —C₀-C₆ alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₆alkyl-NR¹¹COR¹³, where said C₁-C₆ alkyl, is optionally unsubstituted orsubstituted by one or more halo substituents; W³ is selected from thegroup consisting of: H, halo, C₁-C₆ alkyl, —C₀-C₆ alkyl-NR¹¹R¹², —C₀-C₆alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆alkyl-C(O)SR¹⁰, —C₀-C₆ alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆alkyl-OCOR¹³, —C₀-C₆ alkyl-OCONR¹¹R¹², —C₀-C₆ alkyl-NR¹¹CONR¹¹R¹²,—C₀-C₆ alkyl-NR¹¹COR¹³, —C₀-C₆ alkyl-Het, —C₁-C₆ alkyl-Ar and —C₁-C₆alkyl-C₃-C₇ cycloalkyl, wherein said C₁-C₆ alkyl is optionallyunsubstituted or substituted by one or more halo substituents; Q isselected from C₃-C₈ cycloalkyl, Ar and Het; wherein said C₃-C₈cycloalkyl, Ar and Het are optionally unsubstituted or substituted withone or more groups independently selected from halo, cyano, nitro, C₁-C₆alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆alkyl-C(O)SR¹⁰, —C₀-C₆ alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆alkyl-NR¹¹R¹², —C₀-C₆ alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-SO₃H,—C₀-C₆ alkyl-SO₂NR¹¹R¹², —C₀-C₆ alkyl-SO₂R¹⁰, —C₀-C₆ alkyl-SOR¹³, —C₀-C₆alkyl-OCOR¹³, ‘C₀-C₆ alkyl-OC(O)NR¹¹R¹², —C₀-C₆ alkyl-OC(O)OR¹³, —C₀-C₆alkyl-NR¹¹C(O)OR¹³, —C₀-C₆ alkyl-NR¹¹C(O)NR¹¹ R¹², and —C₀-C₆alkyl-NR¹¹COR¹³, where said C₁-C₆ alkyl is optionally unsubstituted orsubstituted by one or more halo substituents; p is 0-8; n is 2-8; m is 0or 1; q is 0 or 1; t is 0 or 1; each R¹ and R² are independentlyselected from H, halo, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆alkyl-NR¹¹R¹², —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-SR¹⁰, —C₁-C₆ alkyl-Het,—C₁-C₆ alkyl-Ar and —C₁-C₆ alkyl-C₃-C₇ cycloalkyl, or R¹ and R² togetherwith the carbon to which they are attached form a 3-5 memberedcarbocyclic or heterocyclic ring, wherein said heterocyclic ringcontains one, or more heteroatoms selected from N, O, and 8, where anyof said C₁-C₆ alkyl is optionally unsubstituted or substituted by one ormore halo substituents; each R³ is the same or different and isindependently selected from halo, cyano, nitro, C₁-C₆ alkyl, C₃-C₆alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-Ar, —C₀-C₆ alkyl-Het, —C₀-C₆alkyl-C₃-C₇ cycloalkyl, —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆ alkyl-C(O)SR¹⁰,—C₀-C₆ alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆ alkyl-NR¹¹R¹², —C₀-C₆alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-SO₃H, —C₀-C₆alkyl-SO₂NR¹¹R¹², —C₀-C₆ alkyl-SO₂R¹⁰, —C₀-C₆ alkyl-SOR¹³, —C₀-C₆alkyl-OCOR¹³, —C₀-C₆ alkyl-OC(O)NR¹¹R¹², —C₀-C₆ alkyl-OC(O)OR¹³, —C₀-C₆alkyl-NR¹¹C(O)OR¹³, —C₀-C₆ alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₆alkyl-NR¹¹COR¹³, wherein said C₁-C₆ alkyl is optionally unsubstituted orsubstituted by one or more halo substituents; each R⁴ and R⁵ isindependently selected from H, halo, C₁-C₆ alkyl, —C₀-C₆ alkyl-Het,—C₀-C₆ alkyl-Ar and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl; R⁶ and R⁷ are eachindependently selected from H, halo, C₁-C₆ alkyl, —C₀-C₆ alkyl-Het,—C₀-C₆ alkyl-Ar and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl; R⁸ and R⁹ are eachindependently selected from H, halo, C₁-C₆ alkyl, —C₀-C₆ alkyl-Het,—C₀-C₆ alkyl-Ar and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl; R¹⁰ is selected fromH, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-Ar, —C₀-C₆alkyl-Het and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl; each R¹¹ and each R¹² areindependently selected from H, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆alkynyl, —C₀-C₆ alkyl-Ar, —C₀-C₆ alkyl-Het and —C₀-C₆ alkyl-C₃-C₇cycloalkyl, or R¹¹ and R¹² together with the nitrogen to which they areattached form a 4-7 membered heterocyclic ring which optionally containsone or more additional heteroatoms selected from N, O, and S; R¹³ isselected from C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆alkyl-Ar, —C₀-C₆ alkyl-Het and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl; R¹⁴ andR¹⁵ are each independently selected from H, C₁-C₆ alkyl, C₃-C₆ alkenyl,C₃-C₆ alkynyl, —C₀-C₆ alkyl-Ar, —C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-C₃-C₇cycloalkyl, —C₀-C₆ alkyl-O—Ar, —C₀-C₆ alkyl-O-Het, —C₀-C₆ alkyl-O—C₃-C₇cycloalkyl, —C₀-C₆ alkyl-S(O)_(x)—C₁-C₆ alkyl, —C₀-C₆ alkyl-S(O)_(x)—Ar,—C₀-C₆ alkyl-S(O)_(x)-Het, —C₀-C₆ alkyl-S(O)_(x)—C₃-C₇ cycloalkyl,—C₀-C₆ alkyl-NH-Het, —C₀-C₆ alkyl-NH—C₃-C₇ cycloalkyl, —C₀-C₆alkyl-N(C₁-C₄ alkyl)-Ar, —C₀-C₆ alkyl-N(C₁-C₄ alkyl)-Het, —C₀-C₆alkyl-N(C₁-C₄ alkyl)-C₃-C₇ cycloalkyl, —C₀-C₆ alkyl-Ar, —C₀-C₆ alkyl-Hetand —C₀-C₆ alkyl-C₃-C₇ cycloalkyl, where x is 0, 1 or 2, or R¹⁴ and R¹⁵,together with the nitrogen to which they are attached, form a 4-7membered heterocyclic ring which optionally contains one or moreadditional heteroatoms selected from N, O, and S, wherein said C₁-C₆alkyl is optionally substituted by one or more of the substituentsindependently selected from the group halo, —OH, —SH, —NH₂,—NH(unsubstituted C₁-C₆ alkyl), —N(unsubstituted C₁-C₆alkyl)(unsubstituted C₁-C₆ alkyl), unsubstituted —OC₁-C₆ alkyl, —CO₂H,—CO₂(unsubstituted C₁-C₆ alkyl), —CONH₂, —CONH(unsubstituted C₁-C₆alkyl), —CON(unsubstituted C₁-C₆ alkyl)(unsubstituted C₁-C₆ alkyl),—SO₃H, —SO₂NH₂, —SO₂NH(unsubstituted C₁-C₆ alkyl) and—SO₂N(unsubstituted C₁-C₆ alkyl)(unsubstituted C₁-C₆ alkyl); R¹⁶ isC₁-C₆ alkyl, —C₀-C₆ alkyl-Ar or —C₀-C₆ alkyl-Het; and R¹⁷ is H, C₁-C₆alkyl, —C₀-C₆ alkyl-Ar or —C₀-C₆ alkyl-Het; and a pharmaceuticallyacceptable salt or solvate thereof.

Another particular embodiment of this invention is directed to acompound of Formula I, II, I-A or II-A, as defined above, wherein X is—COOR¹⁰ and at least one of Y, W¹, W², W³, m, t, R¹, R², R³, R⁴, R5, R⁶,R⁷, R⁸ or R⁹ is defined as follows: wherein Y is —S—, —N(R¹⁰)—, or—C(R⁴)(R⁵)—; or W¹ is C₁-C₆ alkyl or Het, wherein said C₁-C₈ alkyl orand Het is optionally unsubstituted or substituted with one or moregroups independently selected from halo, cyano, nitro, C₁-C₆ alkyl,C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆alkyl-C(O)SR¹⁰, —C₀-C₆ alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆alkyl-NR¹¹R¹², —C₀-C₆ alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-SO₃H,—C₀-C₆ alkyl-SO₂NR¹¹R¹², —C₀-C₆ alkyl-SO₂R¹⁰, —C₀-C₆ alkyl-SOR¹³, —C₀-C₆alkyl-OCOR¹³, —C₀-C₆ alkyl-OC(O)NR¹¹R¹², —C₀-C₆ alkyl-OC(O)OR¹³, —C₀-C₆alkyl-NR¹¹C(O)OR¹³, —C₀-C₆ alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₆alkyl-NR¹¹COR¹³, where said C₁-C₆ alkyl, is optionally unsubstituted orsubstituted by one or more halo substituents; or W² is H, halo, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —C₀-C₆ alkyl-NR¹¹R¹², —C₀-C₆alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆alkyl-C(O)SR¹⁰, C₀-C₆ alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆alkyl-OCOR¹³, —C₀-C₆ alkyl-OCONR R¹², —C₀-C₆ alkyl-NR¹¹CONR¹¹R¹², —C₀-C₆alkyl-NR¹¹COR¹³, —C₀-C₆ alkyl-Het, —C₁-C₆ alkyl-Ar or —C₁-C₆ alkyl-C₃-C₇cycloalkyl, wherein said C₁-C₆ alkyl is optionally unsubstituted orsubstituted by one or more halo substituents, and wherein the C₃-C₇cycloalkyl, Ar and Het moieties of said —C₀-C₆ alkyl-Het, —C₁-C₆alkyl-Ar and —C₁-C₆ alkyl-C₃-C₇ cycloalkyl are optionally unsubstitutedor substituted with one or more groups independently selected from halo,cyano, nitro, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆alkyl-CO₂R¹⁰, —C₀-C₆ alkyl-C(O)SR¹⁰, —C₀-C₆ alkyl-CONR¹¹R¹², —C₀-C₆alkyl-COR¹³, —C₀-C₆ alkyl-NR¹¹R¹², —C₀-C₆ alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰,—C₀-C₆ alkyl-SO₃H, —C₀-C₆ alkyl-SO₂NR¹¹R¹², —C₀-C₆ alkyl-SO₂R¹⁰, —C₀-C₆alkyl-SOR¹³, —C₀-C₆ alkyl-OCOR¹³, —C₀-C₆ alkyl-OC(O)NR¹¹R¹², —C₀-C₆alkyl-OC(O)OR¹³, —C₀-C₆ alkyl-NR¹¹C(O)OR¹³, —C₀-C₆alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₆ alkyl-NR¹¹COR¹³, where said C₁-C₆alkyl, is optionally unsubstituted or substituted by one or more halosubstituents; or W³ is H, halo, C₁-C₆ alkyl, —C₀-C₆ alkyl-NR¹¹R¹²,—C₀-C₆ alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆alkyl-C(O)SR¹⁰, —C₀-C₆ alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆alkyl-OCOR¹³, —C₀-C₆ alkyl-OCONR¹¹R¹², —C₀-C₆ alkyl-NR¹¹CONR¹¹R¹²,—C₀-C₆ alkyl-NR¹¹COR¹³, —C₀-C₆ alkyl-Ar-Het, —C₁-C₆ alkyl-Ar or —C₁-C₆alkyl-C₃-C₇ cycloalkyl, wherein said C₁-C₆ alkyl is optionallyunsubstituted or substituted by one or more halo substituents; or m is0; or t is 1; or at least one of R¹ or R² is halo, C₃-C₆ alkenyl, C₃-C₆alkynyl, —C₀-C₆ alkyl-NR¹¹R¹², —C₀-C₆ alkyl-OR^(10′), —C₀-C₆alkyl-SR^(10′), —C₁-C₆ alkyl-Het, —C₁-C₆ alkyl-Ar and —C₁-C₆ alkyl-C₃-C₇cycloalkyl, or R¹ and R² together with the carbon to which they areattached form a 3-5 membered carbocyclic or heterocyclic ring, whereinsaid heterocyclic ring contains one, or more heteroatoms selected fromN, O, and S, where any of said C₁-C₆ alkyl is optionally unsubstitutedor substituted by one or more halo substituents, where R^(10′), isselected from H, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-Ar, —C₀-C₆alkyl-Het and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl; or at least one R³ is C₃-C₆alkynyl, —C₀-C₆ alkyl-Ar, —C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-C₃-C₇cycloalkyl, —C₀-C₆ alkyl-C(O)SR¹⁰, —C₁-C₆ alkyl-CONR¹¹R¹², —C₁-C₆alkyl-COR¹³, —C₁-C₆ alkyl-SR¹⁰, —C₁-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-SO₃H,—C₀-C₆ alkyl-SO₂NR¹¹R¹², —C₁-C₆ alkyl-SO₂R¹⁰, —C₁-C₆ alkyl-SOR¹³, —C₁-C₆alkyl-OCOR¹³, —C₀-C₆ alkyl-OC(O)NR¹¹R¹², —C₀-C₆ alkyl-OC(O)OR¹³, —C₀-C₆alkyl-NR¹¹C(O)OR¹³, —C₀-C₆ alkyl-NR¹¹C(O)NR¹¹R¹², or —C₀-C₆alkyl-NR¹¹COR¹³, wherein said C₁-C₆ alkyl is optionally unsubstituted orsubstituted by one or more halo substituents; or at least one of R⁴ orR⁵ is halo, C₁-C₆ alkyl, —C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-Ar or —C₀-C₆alkyl-C₃-C₇ cycloalkyl; or at least one of R⁶ or R⁷ is halo, C₁-C₆alkyl, —C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-Ar or —C₀-C₆ alkyl-C₃-C₇cycloalkyl; or R⁹ is halo, —C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-Ar or —C₀-C₆alkyl-C₃-C₇ cycloalkyl; or both R⁸ and R⁹ are each independentlyselected from halo, C₁-C₆ alkyl, —C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-Ar and—C₀-C₆ alkyl-C₃-C₇ cycloalkyl; or and R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶and R¹⁷ are as defined herein.

Yet another particular embodiment of this invention is directed to acompound of Formula I, I-A, II or II-A, as defined above, wherein W¹ andW² are not each independently C₃-C₈ cycloalkyl or aryl or W³ is not H(that is, W¹ and W² are other than C₃-C₈ cycloalkyl or aryl or W³ isother than H) or any one of R⁶ or R⁷ is not H or R⁸ and R⁹ are eachC₁-C₄ alkyl when: X is COOR¹⁰; Z is CH or CR³ and k is 0-4 or Z is N andk is 0-3; p is 0-8; n is 2-8; q is 0 or 1; Q is selected from optionallyunsubstituted or substituted C₃-C₈ cycloalkyl, phenyl and monocyclicHet; each R¹ and R² is independently selected from H, C₁-C₆ alkyl, —OH,—O—C₁-C₆ alkyl, —SH, and —S—C₁-C₆ alkyl; each R³ is the same ordifferent and is independently selected from halo, cyano, nitro,—CONR¹²R¹³, —COR¹⁴, —SR¹¹, —SO₂R¹¹, —SOR¹⁴—OCOR¹⁴ and optionallyunsubstituted or substituted C₁-C₆ alkyl, C₃-C₆ alkenyl, -5-6membered-Het, —C₀-C₆ alkyl-CO₂R¹¹, or —C₀-C₆ alkyl-NR¹²R¹³, where theoptionally unsubstituted or substituted C₃-C₈ cycloalkyl, phenyl andmonocyclic Het; optionally unsubstituted or substituted C₁-C₆ alkyl,C₃-C₆ alkenyl, 5-6 membered-Het, —C₀-C₆ alkyl-CO₂R¹¹, or —C₀-C₆alkyl-NR¹²R¹³, R¹¹, R¹² and R¹³ and R¹⁴ are as defined herein.

Another particular embodiment of this invention is directed to acompound of Formula I, I-A, II or II-A, as defined above, wherein W¹ andW² are not each independently C₃-C₈ cycloalkyl or aryl or W³ is not H(that is, W¹ and W² are other than C₃-C₈ cycloalkyl or aryl or W³ isother than H) when: X is COOR¹⁰; Z is CH, CR³ or N; wherein when Z is CHor CR³, k is 0-4 and when Z is N, k is 0-3; p is 0-8; n is 2-8; q is 0or 1; Q is selected from C₃-C₈ cycloalkyl, phenyl, and monocyclic Het;wherein said C₃-C₈ cycloalkyl, phenyl and monocyclic Het are optionallyunsubstituted or substituted with one or more groups independentlyselected from halo, cyano, nitro, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆alkynyl, —C₀-C₆ alkyl-CO₂R¹¹, —C₀-C₆ alkyl-C(O)SR¹¹, —C₀-C₆alkyl-CONR¹²R¹³, —C₀-C₆ alkyl-COR¹⁴, —C₀-C₆ alkyl-NR¹²R¹³, —C₀-C₆alkyl-SR¹¹, —C₀-C₆ alkyl-OR¹¹, —C₀-C₆ alkyl-SO₃H, —C₀-C₆alkyl-SO₂NR¹²R¹³, —C₀-C₆ alkyl-SO₂R¹¹, —C₀-C₆ alkyl-SOR¹⁴, —C₀-C₆alkyl-OCOR¹⁴, —C₀-C₆ alkyl-OC(O)NR¹²R¹³, —C₀-C₆ alkyl-OC(O)OR¹⁴, —C₀-C₆alkyl-NR¹²C(O)OR¹⁴, —C₀-C₆ alkyl-NR¹²C(O)NR¹²R¹³, and —C₀-C₆alkyl-NR¹²COR¹⁴, where said C₁-C₆ alkyl is optionally unsubstituted orsubstituted by one or more halo substituents; each R¹ and R² isindependently selected from H, C₁-C₆ alkyl, —OH, —O—C₁-C₆ alkyl, —SH,and —S—C₁-C₆ alkyl; each R³ is the same or different and isindependently selected from halo, cyano, nitro, C₁-C₆ alkyl, C₃-C₆alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-Ar, —C₀-C₆ alkyl-Het, —C₀-C₆alkyl-C₃-C₇ cycloalkyl, —C₀-C₆ alkyl-CO₂R¹¹, —C₀-C₆ alkyl-C(O)SR¹¹,—C₀-C₆ alkyl-CONR¹²R¹³; —C₀-C₆ alkyl-COR¹⁴, —C₀-C₆ alkyl-NR¹²R¹³, —C₁-C₆alkyl-SR¹¹, —C₀-C₆ alkyl-OR¹¹, —C₀-C₆ alkyl-SO₃H, —C₀-C₆alkyl-SO₂NR¹²R¹³, —C₀-C₆ alkyl-SO₂R¹¹, —C₀-C₆ alkyl-SOR¹⁴, —C₀-C₆alkyl-OCOR¹⁴, —C₀-C₆ alkyl-OC(O)NR¹²R¹³, —C₀-C₆ alkyl-OC(O)OR¹⁴, —C₀-C₆alkyl-NR¹²C(O)OR¹⁴, —C₀-C₆ alkyl-NR¹²C(O)NR¹²R¹³, and —C₀-C₆alkyl-NR¹²COR¹⁴, wherein said C₁-C₆ alkyl is optionally unsubstituted orsubstituted by one or more halo substituents; each R⁴ and R⁵ isindependently H or C₁-C₄ alkyl; R⁶ and R⁷ are each independently H orC₁-C₄ alkyl; R⁸ and R⁹ are each independently H or C₁-C₄ alkyl; R¹⁰ isselected from H, C₁-C₈ alkyl, C₃-C₈ alkenyl, C₃-C₆ alkynyl, —C₀-C₆alkyl-Ar, —C₀-C₆ alkyl-Het and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl; R¹¹ isselected from H, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆alkyl-Ar, —C₀-C₆ alkyl-Het and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl; each R¹²and each R¹³ are independently selected from H, C₁-C₆ alkyl, C₃-C₆alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-Ar, —C₀-C₆ alkyl-Het and —C₀-C₆alkyl-C₃-C₇ cycloalkyl, or R¹³ and R¹⁴ together with the nitrogen towhich they are attached form a 4-7 membered heterocyclic ring whichoptionally contains one or more additional heteroatoms selected from N,O, and S; and R¹⁴ is selected from C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆alkynyl, —C₀-C₆ alkyl-Ar, —C₀-C₆ alkyl-Het and —C₀-C₆ alkyl-C₃-C₇cycloalkyl; or a pharmaceutically acceptable salt or solvate thereof.

Compounds according to this invention include:2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2,2-dephenylethyl)amino]propoxy}phenyl)-ethanol2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]propoxy}-phenyl)aceticacid, N-oxide;(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]propoxy)bromobenzene;(4-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]propoxy}-bromobenzene;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenylethyl)-{3-[3-(1,2,4-triazol-3-ylmethyl)-phenoxy]-propyl}-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[3-(1,2,3,4-tetrazol-5-ylmethyl)-phenoxy]-propyl}amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2-cyclohexyl-2-phenyl-ethyl)-{3-[3-(1,2,3,4-tetrazol-5-ylmethyl)-phenoxy]-propyl}-amine;(S)-(2-Chloro-3-trifluoromethyl-benzyl)-(2-phenyl-propyl)-{3-[3-(1,2,3,4-tetrazol-3-ylmethyl)-phenoxy]-propyl}-amine;(R)-(2-Chloro-3-trifluoromethyl-benzyl)-(2-phenyl-propyl)-{3-[3-(1,2,3,4-tetrazol-3-ylmethyl)-phenoxy]-propyl}amine;(S)-2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2-phenyl-propyl)amino]propoxy}-phenyl)aceticacid;(R)-2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2-phenyl-propyl)amino]propoxy}-phenyl)aceticacid;2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl]naphthalen-1-ylmethyl-amino]propoxy}-phenyl)aceticacid;2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl]-benzylamino]propoxy}-phenyl)aceticacid;2-(3-{3-[[2-Chloro-3-(trifluoromethyl)-benzyl]phenethylamino]propoxy}-phenyl)aceticacid;2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2-hydroxy-2-phenyl-ethyl)amino]propoxy}-phenyl)aceticacid;2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2-acetoxy-2-phenyl-ethyl)amino]propoxy}-phenyl)aceticacid;2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2-phenoxy-2-phenyl-ethyl)amino]propoxy}-phenyl)aceticacid; Benzoic acid2-[3-(3-carboxymethyl-phenoxy){2-chloro-3-(trifluoromethyl)benzyl}propylamino]-1-phenylethyl ester;(3-{3-[(2-Acetoxy-2-phenyl-ethyl)-(2-chloro-3-trifluoromethyl-benzyl)-amino]-propoxy}-phenyl)-acetcacid methyl ester; Benzoic acid2-[3-(3-methoxycarbonylmethyl-phenoxy){2-chloro-3-(trifluoromethyl)benzyl}propylamino]-1-phenylethyl ester;(3-{4-[(2-Chloro-3-(trifluoromethyl)benzyl)-(2,2-diphenylethyl)-amino]butyl}phenyl)-aceticacid; Preparation of(3-{3-[(4-Fluoro-3-methyl-benzyl)-((R)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-aceticacid;(3-{3-[Benzo[1,3]dioxol-5-ylmethyl-((R)-2-phenyl-propyl)-amino]-propoxy}phenyl)-aceticacid;(3-{3-[(4-tert-Butyl-benzyl)-((R)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-aceticacid;(3-{3-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-((R)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-aceticacid;(3-{3-[(4-Methylsulfanyl-benzyl)-((R)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-aceticacid;(3-{3-[((R)-2-Phenyl-propyl)-(2,4,5-trifluoro-benzyl)-amino]-propoxy}-phenyl)-aceticacid;(3-{3-[((R)-2-Phenyl-propyl)-(5-piperidin-1-yl-furan-2-ylmethyl)-amino]-propoxy}-phenyl)-aceticacid;(3-{3-[(4-Isopropyl-benzyl)-((R)-2-phenyl-propyl)-amino]-propoxy}phenyl)-aceticacid;2-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}phenyl)-propane-1,3-diol;N-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-carbamicacid tert-butyl ester;3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethylamino]-propoxy}-phenylamine;N-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}phenyl)-acetamide;Furan-2-carboxylic acidN-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-amide;N-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-methanesulfonamide;N-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-benzenesulfonamide;1-(2-Chloro-phenyl)-3-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-urea;N-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-N-methyl-amine;N-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-N-methyl-acetamide;Furan-2-carboxylic acidN-(3-(3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-N-methyl-amide;N-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-N-methyl-methanesulfonamide;(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-N-methyl-benzenesulfonamide;3-(2-Chloro-phenyl)-1-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-1-methyl-urea;Benzo[1,3]dioxole-5-carboxylic acidN-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-N-methyl-amide;1-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-3-(3,5-dimethoxy-phenyl)-1-methyl-urea;Propane-1-sulfonic acid(5-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-2-methyl-phenyl)-amide;3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-2-methyl-phenylamine;2-Chloro-5-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenylamine;3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-cyclopentyl-amine,(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-isopropyl-amine,Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-ethyl-amine,(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-(3-methyl-butyl)-amine,(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-isobutyl-amine,(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-(2,2,2-trifluoroethyl)-amine,(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-cyclopropylmethy-l-amine,(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-(2-ethyl-butyl)-amine,(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-(2,2-dimethyl-propyl)-amine,(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-hexyl-amine,Butyl-(3-{3[(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-amine,[1-(3-{3-[(2-Chloro-3-(trifluoromethyl)-benzyl)-(2,2-diphenylethyl)-amino]-propoxy}-phenyl-piperidine-4-carboxylicacid,[1-(3-{3-[(2-Chloro-3-(trifluoromethyl)-benzyl)-(2,2-diphenylethyl)-amino]-propoxy}-phenyl-piperidine-4-yl-aceticacid;[4-(3-{3-[(2-Chloro-3-(trifluoromethyl)-benzyl)-(2,2-diphenylethyl-amino]-propoxy}-phenyl)-piperidin-1-yl]-aceticacid,rac-±-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(trifluoro-phenyl-propyl)-amino]-propoxy}-phenyl)-aceticacid;rac-±-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2-dimethylamino-2-phenyl-ethyl)-amino]-propoxy}-phenyl)-aceticacid;rac-±-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2-morpholin-4-yl-2-phenyl-ethyl)-amino]-propoxy}-phenyl)-aceticacid;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(6-morpholin-4-yl-pyridin-2-yloxy)-propyl]-amine;[3-(6-Chloro-pyridin-2-yloxy)-propyl](2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[6-(4-methyl-piperazin-1-yl)-pyridin-2-yloxy]-propyl}-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(6-piperazin-1-yl-pyridin-2-yloxy)-propyl]-amine;[4-(6-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-pyridin-2-yl)-piperazin-1-yl]-aceticacid;2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl]((S)-2-phenyl-propyl)amino]-(R)-1-methyl-propoxy}-phenyl)aceticacid;2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl]((S)-2-phenyl-propyl)amino]-(R)-1-methyl-propoxy}-phenyl)ethanol;2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl]((S)-2-phenyl-propyl)amino]-(R)-2-methyl-propoxy}-phenyl)aceticacid;2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl]((S)-2-phenyl-propyl)amino]-(R)-2-methyl-propoxy}-phenyl)ethanol;2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl]((R)-2-phenyl-propyl)amino]-(R)-2-methyl-propoxy}-phenyl)aceticacid;2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl]((R)-2-phenyl-propyl)amino]-(R)-2-methyl-propoxy}-phenyl)ethanol;(R)-2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]-2-methyl-propoxy}-phenyl)ethanol;3-{3-[(3-Chloro-2-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy-N,N-dimethyl-benzenesulfonamide,Cyclopropanecarboxylic acid3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-benzylamide;N-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-benzyl)-isobutyramide;Acetic acid(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-benzylcarbamoyl)-methylester; N--(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-benzyl)-propionamide;2,5-Dimethyl-2-H-pyrazole-3-carboxylic acid3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-benzylamide;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-(3-o-tolyloxy-propyl)-amine;2-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-benzonitrile;[3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}benzonitrile;[3-(3-Chloro-phenoxy)-propyl]-(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(2-methoxy-phenoxy)-propyl]-amine;[3-(2-Chloro-phenoxy)-propyl]-(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-(3-phenoxy-propyl)-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-isopropyl-phenoxy)-propyl]-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(4-methoxy-phenoxy)-propyl]-amine;3-{3-[(Chloro-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenol;2-{3-[(Chloro-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenol;3-{3-[(Chloro-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenylamine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-trifluoromethyl-phenoxy)-propyl]-amine;1-(3-{3-[(Chloro-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-ethanone;(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-phenyl-amine;[3-(Benzo[1,3]dioxol-5-yloxy)-propyl]-(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-(3-m-tolyloxy-propyl)-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-methoxy-phenoxy)-propyl]-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-isobutyl-phenoxy)-propyl]-amine;[3-(3-Butyl-phenoxy)-propyl]-(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amine;(2-Chloro-3-trifluoromethyl-benzyl)-{3-[3-(2,2-dimethyl-propyl)-phenoxy]-propyl}-(2,2-diphenyl-ethyl)-amine;(4-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-benzyl)-methyl-amine;(2-Chloro-3-trifluoromethyl-benzyl)-[3-(4-dimethylaminomethyl-phenoxy)-propyl]-(2,2-diphenyl-ethyl)-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(4-morpholin-4-ylmethyl-phenoxy)-propyl]-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[4-(4-methyl-piperazin-1-ylmethyl)-phenoxy]-propyl}-amine;(3-{3-[(Chloro-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-benzyl)-methyl-amine;(2-Chloro-3-trifluoromethyl-benzyl)-[3-(3-dimethylaminomethyl-phenoxy)-propyl]-(2,2-diphenyl-ethyl)-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-morpholin-4-ylmethyl-phenoxy)-propyl]-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[3-(4-methyl-piperazin-1-ylmethyl)-phenoxy]-propyl}-amine;(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-benzyl)-isopropyl-amine;{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-4-trifluoromethyl-phenylamine;{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-4-methyl-phenylamine;Ethanesulfonic acid(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-4-methyl-phenyl)-amide;Propane-2-sulfonic acid(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-4-methyl-phenyl)-amide;Methanesulfonic acid(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-4-methyl-phenyl)-amide;2,2,2-Trifluoro-ethanesulfonic acid(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-4-methyl-phenyl)-amide;Ethanesulfonic acid(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-phenyl)-amide;2,2,2-Trifluoro-ethanesulfonic acid(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-phenyl)-amide;N-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-phenyl)-1,1,1-trifluoro-methanesulfonamide;Propane-2-sulfonic acid(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-phenyl)-amide;{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-4-methoxy-phenylamine;Ethanesulfonic acid(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-4-methoxy-phenyl)-amide;(2-Chloro-3-trifluoromethyl-benzyl)-{3-[3-(2-morpholin-4-yl-ethyl)-phenoxy]-propyl}-((S)-2-phenyl-propylamine;(2-Chloro-3-trifluoromethyl-benzyl)-{3-[3-(2-ethylamino-ethyl)-phenoxy]-propyl}((S)-2-phenyl-propyl)-amine;(3-{-(R)-3-[(2-Chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-amino]-butoxy}-phenyl)-aceticacid;(3{(S)-3-[(2-Chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-amino]-butoxy}-phenyl)-aceticacid;2-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-ethanol;2-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-2-methyl-propionicacid;2-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-((R)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-2-methyl-propionicacid;(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2-thiophen-3-yl-propyl)-amino]-propoxy}-phenyl)-aceticacid;2-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2-thiophen-3-yl-propyl)-amino]-propoxy}-phenyl)-ethanol;(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2-thiophen-2-yl-propyl)-amino]-propoxy}-phenyl)-aceticacid;(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2-pyridin-2-yl-propyl)-amino]-propoxy}-phenyl)-aceticacid;[3-(3-{(2-Chloro-3-trifluoromethyl-benzyl)-[2-(4-methyl-pyridin-2-yl)-propyl]-amino}-propoxy)-phenyl]-aceticacid;[3-(3{(2-Chloro-3-trifluoromethyl-benzyl)-[3,3,3-trifluoro-2-(1H-pyrrol-2-yl)-propyl]-amino}-propoxy)-phenyl]-aceticacid;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-(3-{3-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenoxy}-propyl)-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[3-(2-methylamino-ethyl)-phenoxy]-propyl}-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-{2-[(1H-imidazol-2-ylmethyl)-amino]-ethyl}-phenoxy)-propyl]-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[3-(2-ethylamino-ethyl)-phenoxy]-propyl}-amine;[3-(3-{2-[(5-Bromo-thiophen-2-ylmethyl)-amino]-ethyl}-phenoxy)-propyl]-(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-{2-[(thiophen-2-ylmethyl)-amino]-ethyl}-phenoxy)-propyl]-amine;(2-Chloro-3-trifluoromethyl-benzyl)-{3-[3-(2-dimethylamino-ethyl)-phenoxy]-propyl}-(2,2-diphenyl-ethyl)-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[3-(2-pyrrolidin-1-yl-ethyl)-phenoxy]-propyl}-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl){3-[3-(2-morpholin-4-yl-ethyl)-phenoxy]-propyl}-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl){(R)-1-methyl-3-[3-(2-morpholin-4-yl-ethyl)-{phenoxy]-propyl}-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{(R)-2-methyl-3-[3-(2-morpholin-4-yl-ethyl)-phenoxy]-propyl}-amine;{3-[3-(2-Amino-ethyl)-phenoxy]-propyl}-(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amine;[2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-ethyl]-isopropyl-amine;[2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-ethyl]-propyl-amine;2-[2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-ethylamino]-ethanol;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-{2-[(1-methyl-1H-imidazol-2-ylmethyl)-amino]-ethyl}-phenoxy)-propyl]-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[3-(2-thiomorpholin4-yl-ethyl)-phenoxy]-propyl}-amine;[2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-ethylamino]-aceticacid;[2-(3-{(R)-3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-butoxy}-phenyl)-ethylamino]-aceticacid;{[2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-ethyl]-methyl-amino}-aceticacid;2-[2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-ethylamino]-2-methyl-propionicacid;(S)-2-[2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-ethylamino]-propionicacid;(R)-1-[2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-ethyl]-pyrrolidine-2-carboxylicacid;(S)-1-[2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-ethyl]-pyrrolidine-2-carboxylicacid;[2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-ethyl]-pyrimidin-2-yl-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-morpholin-4-yl-phenoxy)-propyl]-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-piperidin-1-yl-phenoxy)-propyl]-amine;(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-diethyl-amine;(2-Chloro-3-trifluoromethyl-benzyl)-{3-[3-(2,5-dimethyl-pyrrol-1-yl)-phenoxy]-propyl}-(2,2-diphenyl-ethyl)-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-piperazin-1-yl-phenoxy)-propyl]-amine;(2-Chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-[3-(3-piperazin-1-yl-phenoxy)-propyl]-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[(R)-2-methyl-3-(3-piperazin-1-yl-phenoxy)-propyl]-amine,(2-Chloro-3-trifluoromethyl-benzyl)-isobutyl-[3-(3-piperazin-1-yl-phenoxy)-propyl]-amine;[4-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-piperazin-1-yl]-aceticacid;[4-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-piperazin-1-yl]-aceticacid;[4-(3-((R)-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-methyl-propoxy}-phenyl)-piperazin-1-yl]-aceticacid;[4-(3-(3-[(2-chloro-3-trifluoromethyl-benzyl)-isobutyl-amino]-propoxy}-phenyl)-piperazin-1-yl]-aceticacid;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[3-(4-methyl-piperazin-1-yl)-phenoxy]-propyl}-amine,(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-pyrrolidin-1-yl-phenoxy)-propyl]-amine;(3-(3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenylamino)-aceticacid;[(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-N-methyl-amino]-aceticacid;N-(2,2-Diphenylethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-[3-(2-methyl-2-aminopropyl)phenoxy]propylamine,N-(2,2-Diphenylethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-[2-hydroxymethyl]phenoxy)propylamine,N-(2,2-Diphenylethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-[2-hydroxy-2-methylpropyl]phenoxy)propylamine;N-(2,2-Diphenylethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-N-methylsulfonamidophenoxy)propylamine,N-(2-[2-Chlorophenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,N-(2-[3-Chlorophenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,N-(2-[4-Chlorophenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,N-(2-[2-Methoxyphenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,N-(2-[4-Methoxyphenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,N-(2-Phenyl-4-methylpentyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,N-(2-Phenylbutyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,N-(2-[2-Methyl-2-phenyl]propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,N-(2-Phenyl-3-methylbutyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,N-(2-Phenylhexyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,N-(2-Phenyl-3-butynyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine;(S)-N-(2-Phenyl-2-methoxyethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,(R)-N-(2-Phenyl-2-methoxyethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,(R)-N-(2-Phenyl-2-methoxyethyl)-N-2-chloro-3-trifluoromethylbenzyl)-3-(3-[2-hydroxy-2-methylpropyl]phenoxy)propylamine;2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2-methyl-propyl)amino]-propoxy}-phenyl)aceticacid;1-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-cyclobutanecarboxylicacid;1-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy)-phenyl)-cyclopentanecarboxylicacid;1-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-cyclopropanecarboxylicacid;

and a stereoisomer, a stereoisomeric mixture or racemate thereof and apharmaceutically acceptable salt or solvate thereof.

Preferred compounds of this invention include:

-   2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2,2-dephenylethyl)amino]propoxy}phenyl)-ethanol,-   (2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenylethyl)-{3-[3-(1,    2,4-triazol-3-ylmethyl)-phenoxy]-propyl}-amine,-   (2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[3-(1,2,3,4-tetrazol-5-ylmethyl)-phenoxy]-propyl}-amine,-   (2-chloro-3-trifluoromethyl-benzyl)-(2-cyclohexyl-2-phenyl-ethyl)-{3-[3-(1,2,3,4-tetrazol-5-ylmethyl)-phenoxy]-propyl}-amine,-   (S)-(2-chloro-3-trifluoromethyl-benzyl)-(2-phenyl-propyl)-{3-[3-(1,2,3,4-tetrazol-3-ylmethyl)-phenoxy]-propyl}-amine,-   (R)-(2-chloro-3-trifluoromethyl-benzyl)-(2-phenyl-propyl)-{3-[3-(1,2,3,4-tetrazol-3-ylmethyl)-phenoxy]-propyl}-amine,-   2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl]-benzylamino]propoxy}-phenyl)acetic    acid,-   2-(3-{3-[[2-chloro-3-(trifluoromethyl)-benzyl]phenethylamino]propoxy}-phenyl)acetic    acid,-   2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2-hydroxy-2-phenyl-ethyl)amino]propoxy}-phenyl)acetic    acid,-   2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2-acetoxy-2-phenyl-ethyl)amino]propoxy}-phenyl)acetic    acid,-   2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2-phenoxy-2-phenyl-ethyl)amino]propoxy}-phenyl)acetic    acid,-   (3-{3-[(2-acetoxy-2-phenylethyl)₂-chloro-3-trifluoromethyl-benzyl)-amino]-propoxy}-phenyl)-acetic    acid methyl ester,-   benzoic acid    2-[3-(3-methoxycarbonylmethyl-phenoxy){2-chloro-3-(trifluoromethyl)benzyl}propylamino]-1-phenyl    ethyl ester,-   (3-[(2-chloro-3-trifluoromethyl)benzyl)-(2,2-diphenylethyl)-amino]butyl}phenyl)-acetic    acid,-   2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2,2-dephenylethyl)amino]propoxy}phenyl)-ethanol,-   (2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenylethyl)-{3-[3-(1,2,4-triazol-3-ylmethyl)-phenoxy]-propyl}-amine,-   (2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[3-(1,2,3,4-tetrazol-5-ylmethyl)-phenoxy]-propyl}-amine,-   (S)-(2-chloro-3-trifluoromethyl-benzyl)-(2-phenyl-propyl)-{3-[3-(1,2,3,4-tetrazol-3-ylmethyl)-phenoxy]-propyl}-amine,-   (R)-(2-chloro-3-trifluoromethyl-benzyl)-(2-phenyl-propyl)-{3-[3-(1,2,3,4-tetrazol-3-ylmethyl)-phenoxy]-propyl}-amine,-   (S)-2-(33-[[2-chloro-3-(trifluoromethyl)benzyl](2-phenyl-propyl)amino]propoxy}-phenyl)acetic    acid,-   furan-2-carboxylic acid    N-(33-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-amide,-   (R)-2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2-phenyl-propyl)amino]propoxy}-phenyl)acetic    acid,-   2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2-acetoxy-2-phenyl-ethyl)amino]propoxy}-phenyl)acetic    acid,-   (3-{3-[(2-Acetoxy-2-phenyl-ethyl)-(2-chloro-3-trifluoromethyl-benzyl)-amino]-propoxy}-phenyl)-acetic    acid methyl ester,-   (3-(4-[(2-chloro-3-(trifluoromethyl)benzyl)-(2,2-diphenylethyl)-amino]butyl}phenyl)-acetic    acid,-   1-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-cyclobutanecarboxylic    acid,-   N-(2,2-diphenylethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-[2-hydroxy-2-methylpropyl]phenoxy)propylamine,-   (2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-{2-[(1H-imidazol-2-ylmethyl)-amino]-ethyl}-phenoxy)-propyl]-amine,-   N-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-methanesulfonamide,-   N-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-N-methyl-amine,-   [2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-ethylamino]-acetic    acid,-   (R)-1-[2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-ethyl]-pyrrolidine-2-carboxylic    acid,-   N-(2-[3-chlorophenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,-   (2-chloro-3-trifluoromethyl-benzyl)-{3-[3-(2-morpholin-4-yl-ethyl)-phenoxy]-propyl}-((S)-2-phenyl-propyl    amine,-   [4-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}phenyl)-piperazin-1-yl]-acetic    acid,-   2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-2-methyl-propionic    acid,-   (2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[3-(4-methyl-piperazin-1-yl)-phenoxy]-propyl}-amine,-   (3-{(R)-3-[(2-chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-amino]-butoxy}-phenyl)-acetic    acid,-   [1-(3-{3-[(2-chloro-3-(trifluoromethyl)-benzyl)-(2,2-diphenylethyl)-amino]-propoxy}-phenyl-piperidine-4-carboxylic    acid,-   [4-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-piperazin-1-yl]-acetic    acid,-   [4-(3-{(R)-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-methyl-propoxy}-phenyl)-piperazin-1-yl]-acetic    acid,

and a stereoisomer, a stereoisomeric mixture or racemate thereof and apharmaceutically acceptable salt or solvate thereof.

More preferred compounds of this invention include:

-   2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2,2-dephenylethyl)amino]propoxy}phenyl)-ethanol,-   (2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenylethyl)-{3-[3-(1,2,4-triazol-3-ylmethyl)-phenoxy]-propyl}-amine,-   (2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[3-(1,2,3,4-tetrazol-5-ylmethyl)-phenoxy]-propyl}-amine,-   (S)-(2-chloro-3-trifluoromethyl-benzyl)-(2-phenyl-propyl)-{3-[3-(1,2,3,4-tetrazol-3-ylmethyl)-phenoxy]-propyl}-amine,-   (R)-(2-chloro-3-trifluoromethyl-benzyl)-(2-phenyl-propyl)-{3-[3-(1,2,3,4-tetrazol-3-ylmethyl)-phenoxy]-propyl}-amine,-   (S)-2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2-phenyl-propyl)amino]propoxy}-phenyl)acetic    acid,-   (R)-2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2-phenyl-propyl)amino]propoxy}-phenyl)acetic    acid,-   2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2-acetoxy-2-phenyl-ethyl)amino]propoxy}-phenyl)acetic    acid,-   (3-{3-[(2-Acetoxy-2-phenyl-ethyl)-(2-chloro-3-trifluoromethyl-benzyl)-amino]-propoxy}-phenyl)-acetic    acid methyl ester,-   (3-{4-[(2-chloro-3-(trifluoromethyl)benzyl)-(2,2-diphenylethyl)-amino]butyl}phenyl)-acetic    acid,-   1-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-cyclobutanecarboxylic    acid,-   N-(2,2-diphenylethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-[2-hydroxy-2-methylpropyl]phenoxy)propylamine,-   (2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-{2-[(1H-imidazol-2-ylmethyl)-amino]-ethyl}-phenoxy)-propyl]-amine,-   N-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-methanesulfonamide,-   N-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-N-methyl-amine,-   [2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-ethylamino]-acetic    acid,-   (R)-1-[2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-ethyl]-pyrrolidine-2-carboxylic    acid,-   furan-2-carboxylic acid    N-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-amide,-   N-(2-[3-chlorophenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,-   (2-chloro-3-trifluoromethyl-benzyl)-{3-[3-(2-morpholin-4-yl-ethyl)-phenoxy]-propyl}-((S)-2-phenyl-propyl    amine,-   [4-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-piperazin-1-yl]-acetic    acid,-   2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-2-methyl-propionic    acid,-   (2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[3-(4-methyl-piperazin-1-yl)-phenoxy]-propyl}-amine,-   (3-{(R)-3-[(2-chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-amino]-butoxy}-phenyl)-acetic    acid,-   [1-(3-{3-[(2-chloro-3-(trifluoromethyl)-benzyl)-(2,2-diphenylethyl)-amino]-propoxy}-phenyl-piperidine-4-carboxylic    acid,-   [4-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-piperazin-1-yl]-acetic    acid,-   [4-(3-{(R)-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-methyl-propoxy}-phenyl)-piperazin-1-yl]-acetic    acid,

and a stereoisomer, a stereoisomeric mixture or racemate thereof and apharmaceutically acceptable salt or solvate thereof.

The term “LXR modulator,” as used herein, means a small molecule thatmodulates the biological activities of LXRα and/or LXRβ. Morespecifically, such an LXR modulator either enhances or inhibits thebiological activities of LXR. If such a modulator partially orcompletely enhances the biological activities of LXR, it is a partial orcomplete LXR agonist, respectively. If such a modulator partially orcompletely inhibits the biological activities of LXR, it is a partial orcomplete LXR agonist, respectively. Preferably, the LXR modulatorcompounds of this invention are LXR agonists. As used herein, the term“LXR agonist” refers to compounds which achieve at least 20% activationof LXR relative to 24(S),25-epoxycholesterol, the appropriate positivecontrol in the HTRF assay described below in Test Method 1. It should benoted that to show activity in the specific Test Methods describedherein, the LXR modulator compound must bind to the LXR nuclear receptorand recruit the specific peptide derived from the coactivator protein,SRC1, to the modulator compound-bound LXR complex. The compounds of thisinvention that form an LXR-modulator compound-complex may also recruitat least one or more of the other >80 known different nuclear receptorcofactors. Recruiter peptides derived from any of these other nuclearreceptor cofactors may be similarly prepared and assayed according toknown procedures.

Compounds that are closely structurally related to the compounds ofExamples 1-201 have been prepared that do not demonstrate at least 20%recruitment of the SRC1-derived peptide. It is anticipated, however,that such compounds do bind to LXR. It is further anticipated that suchan LXR-modulator compound-complex will recruit at least one or more ofthe other >80 known different nuclear receptor cofactors. Examples ofsuch compounds include:

{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]propoxy}benzenehaving an X—(CR¹R²)_(p)— group wherein p is 0, k is 0, and X is asfollows (the designated position of the X group is relative to the—Y—(CR⁴R⁵)_(n)— group on the benzene moiety): 4-cyano, 4-isopropyl,4-methyl, 4-trifluoromethyl, 4-chloro, 3-amino, 4-(phenylamino)-,4-benzyloxy-, 4-acetyl, 3-(phenylamino)methyl-, 4-phenylaminomethyl-,4-isopropylaminomethyl-, 4-tert-butoxycarbonyl-N-methyl-amino-,3,5-di-trifluoromethylphenylcarbonyl-N-methyl-amino-,4-phenylamidosulfonyl-(Ph-N(H)O₂S—), and4-phenylsulfonylamido-(Ph-SO₂N(H)—);

{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]propoxy}benzenehaving an X—(CR¹R²)_(p)— and an (R³)_(k) group, wherein p is 0, k is 1,and X and R³ are as follows (the designated position of the X and R³groups are relative to the —Y—(CR⁴R⁵)_(r)-group on the benzene moiety):2-trifluoromethyl-5-methyl-sulfonylamido-(H₃C—SO₂N(H)—),2-trifluoromethyl-5-n-propyl-sulfonylamido-,2-trifluoromethyl-5-(3-chloro-n-prop-1-yl)-sulfonylamido-,2-trifluoromethyl-5-trifluoromethyl-sulfonylamido-,2-trifluoromethyl-5-iso-propyl-sulfonylamido-,2-methyl-5-tert-butoxycarbonylamino-,2-methyl-5-iso-propyl-sulfonylamido-,2-methyl-5-trifluoromethyl-sulfonylamido-,2-methyl-5-ethyl-sulfonylamido-,2-methyl-5-(2,2,2-trifluoroethyl)-sulfonylamido-,4-methyl-3-ethyl-sulfonylamido-, 2-methoxy-5-tert-butoxycarbonylamino-,2-methoxy-5-tert-butyl-sulfonylamido-,2-methoxy-5-(2,2,2-trifluoroethyl)-sulfonylamido-,2-methoxy-5-iso-propyl-sulfonylamido-, and2-methoxy-5-methyl-sulfonylamido-;

{3-[(R)-3-(2,2-diphenylethyl)amino)-2-methyl-propoxy}-phenyl}-aceticacid having a Q-(CR⁸R⁹)_(q)— group consisting of Q-(CH₂)— wherein Q isfuran-2-yl and 5-chloro-thien-2-yl;

{3-[3-(R)-2-(phenylpropylamino)-propoxy}-phenyl)acetic acid, where R¹and R² are H and having the Q-(CR³R⁹)_(q)— group Q-(CH₂)— wherein Q isquinolin-8-yl, 2-methoxy-naphth-1-yl, 3,5-dimethoxy-phenyl-,3,5-dimethyl-phenyl-, 2,5-dimethoxy-phenyl-, 2,4,6-trimethoxy-phenyl-,4-(n-hexyloxy)-phenyl-, 4-benzyloxy-phenyl-,3-(4-methoxy-phenoxy)-phenyl-, 3-methoxy-4-benzyloxy-phenyl-,4-[(3-N,N-dimethylamino)prop-1-yloxy)-phenyl-, 4-acetylamino-phenyl-; orwhere R¹ and R² are methyl and Q-(CR⁸R⁹)_(q)— is the group Q-(CH₂)—wherein Q is 2-chloro-3-trifluoromethyl-phenyl-;

{3-[3-(S)-2-(phenylpropylamino)-propoxy}-phenyl}-acetic acid, where R¹and R² are H and having the Q-(CR⁸R⁹)_(q)— group Q-(CH₂)— wherein Q is2,6-dimethoxy-phenyl-, 3-cyanophenyl-, furan-2-yl-, and6-chloro-benzo[1,3]diox-5-yl; and

(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl]-(2-phenyl-propyl)amino]-propoxy}-phenyl)aceticacid where the phenyl moiety of the 2-phenylpropyl group is3-methoxyphenyl or 2-methoxyphenyl.

The compounds of this invention are useful for a variety of medicinalpurposes. The compounds of this invention may be used in methods for theprevention or treatment of LXR mediated diseases and conditions. Thisinvention further provides compounds of this invention for use in thepreparation of a medicament for the prevention or treatment of an LXRmediated disease or condition. LXR mediated diseases or conditionsinclude inflammation, cardiovascular disease including atherosclerosis,arteriosclerosis, hypercholesteremia, and hyperlipidemia. In particular,the compounds of this invention are useful in the treatment andprevention of inflammation, cardiovascular disease includingatherosclerosis and hypercholesteremia.

The present invention also provides a method for increasing reversecholesterol transport, compounds of this invention for increasingreverse cholesterol transport and the use of compounds of this inventionfor the preparation of a medicament for increasing reverse cholesteroltransport. Lipoprotein metabolism is a dynamic process comprised ofproduction of triglyceride rich particles from the liver (as VLDL),modification of these lipoprotein particles within the plasma (VLDL toIDL to LDL) and clearance of the particles from the plasma, again by theliver. This process provides the transport of triglycerides and freecholesterol to cells of the body. Reverse cholesterol transport is theproposed mechanism by which peripheral cholesterol is returned to theliver from extra-hepatic tissue. The process is carried out by HDLcholesterol. The combination of lipoprotein production (VLDL, HDL) fromthe liver, modification of particles (all) within the plasma andsubsequent clearance back to the liver, accounts for the steady statecholesterol concentration of the plasma. Without wishing to be bound byany particular theory, it is currently believed that the compounds ofthis invention increase reverse cholesterol transport by increasingcholesterol efflux from the arteries.

Additionally, this invention provides a method for inhibitingcholesterol absorption, compounds of this invention for inhibitingcholesterol absorption and the use of compounds of this invention forthe preparation of a medicament for inhibiting cholesterol absorption.This invention also provides a method for increasing reverse cholesteroltransport, compounds of this invention for increasing reversecholesterol transport and the use of compounds of this invention for thepreparation of a medicament for increasing reverse cholesteroltransport.

The compounds of this invention may also be useful for the prevention ortreatment of inflammation and neurodegenerative diseases or neurologicaldisorders. Accordingly, this invention also provides a method forpreventing or treating inflammation (See A. J. Fowler et al., J. Invest.Dermatol., 2003 February, 120 (2): 246-255 and S. B. Joseph, et al. NatMed., 2003 February, 9 (2): 213-219) and a method for preventing ortreating neurodegenerative diseases or neurological disorders,particularly neurodegenerative diseases or disorders characterized byneuron degeneration, neuron injury or impaired plasticity orinflammation in the CNS (as disclosed in U.S. Provisional patentapplication No. 60/368,424, filed 27 Mar., 2002). Particular diseases orconditions that are characterized by neuron degeneration andinflammation, and thus benefiting from the growth and/or repair ofneurons include stroke, Alzheimer's disease, fronto-temporal dementias(tauopathies), peripheral neuropathy, Parkinson's disease, dementia withLewy bodies, Huntington's disease, amyotrophic lateral sclerosis andmultiple sclerosis. Diseases or conditions that are characterized byneuron degeneration and/or impaired plasticity include psychiatricdisorders such as schizophrenia and depression. Particular diseases orconditions that are characterized by neuronal injury include thoseconditions associated with brain and/or spinal cord injury, includingtrauma.

The methods of the present invention are useful for the treatment ofanimals including mammals generally and particularly humans. The presentinvention further provides the use of compounds of this invention forthe preparation of a medicament for increasing reverse cholesteroltransport

The methods of the present invention comprise the step of administeringa therapeutically effective amount of the compound of this invention. Asused herein, the term “therapeutically effective amount” refers to anamount of the compound of this invention that is sufficient to achievethe stated effect. Accordingly, a therapeutically effective amount of acompound of this invention used in the method for the prevention ortreatment of LXR mediated diseases or conditions will be an amountsufficient to prevent or treat the LXR mediated disease or condition.Similarly, a therapeutically effective amount of a compound of thisinvention for use in the method of increasing reverse cholesteroltransport will be an amount sufficient to increase reverse cholesteroltransport

The amount of a compound of this invention or pharmaceuticallyacceptable salt or solvate thereof, which is required to achieve thedesired biological effect will depend on a number of factors such as theuse for which it is intended, the means of administration, and therecipient, and will be ultimately at the discretion of the attendantphysician or veterinarian. In general, a typical daily dose for thetreatment of LXR mediated diseases and conditions in a human, forinstance, may be expected to lie in the range of from about 0.01 mg/kgto about 100 mg/kg. This dose may be administered as a single unit doseor as several separate unit doses or as a continuous infusion. Similardosages would be applicable for the treatment of other diseases,conditions and therapies including increasing reverse cholesteroltransport, and inhibiting cholesterol absorption.

In another embodiment, the present invention provides pharmaceuticalcompositions comprising a compound of this invention or apharmaceutically acceptable salt or solvate thereof, as the activeingredient, and at least one pharmaceutical carrier or diluent. Thesepharmaceutical compositions may be used in the prophylaxis and treatmentof the foregoing diseases or conditions and in cardiovascular therapiesas mentioned above. The carrier must be pharmaceutically acceptable andmust be compatible with, i.e. not have a deleterious effect upon, theother ingredients in the composition. The carrier may be a solid orliquid and is preferably formulated as a unit dose formulation, forexample, a tablet which may contain from 0.05 to 95% by weight of theactive ingredient.

Possible formulations include those suitable for oral, sublingual,buccal, parenteral (for example subcutaneous, intramuscular, orintravenous), rectal, topical including transdermal, intranasal andinhalation administration. Most suitable means of administration for aparticular patient will depend on the nature and severity of the diseaseor condition being treated or the nature of the therapy being used andon the nature of the active compound, but where possible, oraladministration is preferred for the prevention and treatment of LXRmediated diseases and conditions.

Formulations suitable for oral administration may be provided asdiscrete units, such as tablets, capsules, cachets, lozenges, eachcontaining a predetermined amount of the active compound; as powders orgranules; as solutions or suspensions in aqueous or non-aqueous liquids;or as oil-in-water or water-in-oil emulsions.

Formulations suitable for sublingual or buccal administration includelozenges comprising the active compound and, typically a flavored base,such as sugar and acacia or tragacanth and pastilles comprising theactive compound in an inert base, such as gelatin and glycerine orsucrose acacia.

Formulations suitable for parenteral administration typically comprisesterile aqueous solutions containing a predetermined concentration ofthe active compound; the solution is preferably isotonic with the bloodof the intended recipient Additional formulations suitable forparenteral administration include formulations containingphysiologically suitable co-solvents and/or complexing agents such assurfactants and cyclodextrins. Oil-in-water emulsions are also suitableformulations for parenteral formulations. Although such solutions arepreferably administered intravenously, they may also be administered bysubcutaneous or intramuscular injection.

Formulations suitable for rectal administration are preferably providedas unit-dose suppositories comprising the active ingredient in one ormore solid carriers forming the suppository base, for example, cocoabutter.

Formulations suitable for topical or intranasal application includeointments, creams, lotions, pastes, gels, sprays, aerosols and oils.Suitable carriers for such formulations include petroleum jelly,lanolin, polyethyleneglycols, alcohols, and combinations thereof.

Formulations of the invention may be prepared by any suitable method,typically by uniformly and intimately admixing the active compound withliquids or finely divided solid carriers or both, in the requiredproportions and then, if necessary, shaping the resulting mixture intothe desired shape.

For example a tablet may be prepared by compressing an intimate mixturecomprising a powder or granules of the active ingredient and one or moreoptional ingredients, such as a binder, lubricant, inert diluent, orsurface active dispersing agent, or by molding an intimate mixture ofpowdered active ingredient and inert liquid diluent.

Suitable formulations for administration by inhalation include fineparticle dusts or mists which may be generated by means of various typesof metered dose pressurized aerosols, nebulisers, or insufflators.

For pulmonary administration via the mouth, the particle size of thepowder or droplets is typically in the range 0.5-10 μM, preferably 1-5μM, to ensure delivery into the bronchial tree. For nasaladministration, a particle size in the range 10-500 μM is preferred toensure retention in the nasal cavity.

Metered dose inhalers are pressurized aerosol dispensers, typicallycontaining a suspension or solution formulation of the active ingredientin a liquefied propellant. During use, these devices discharge theformulation through a valve adapted to deliver a metered volume,typically from 10 to 150 μL, to produce a fine particle spray containingthe active ingredient. Suitable propellants include certainchlorofluorocarbon compounds, for example, dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane and mixtures thereof.The formulation may additionally contain one or more co-solvents, forexample, ethanol surfactants, such as oleic acid or sorbitan trioleate,anti-oxidants and suitable flavoring agents. Nebulisers are commerciallyavailable devices that transform solutions or suspensions of the activeingredient into a therapeutic aerosol mist either by means ofacceleration of a compressed gas typically air or oxygen, through anarrow venturi orifice, or by means of ultrasonic agitation. Suitableformulations for use in nebulisers consist of the active ingredient in aliquid carrier and comprising up to 40% w/w of the formulation,preferably less than 20% w/w. The carrier is typically water or a diluteaqueous alcoholic solution, preferably made isotonic with body fluids bythe addition of, for example, sodium chloride. Optional additivesinclude preservatives if the formulation is not prepared sterile, forexample, methyl hydroxy-benzoate, anti-oxidants, flavoring agents,volatile oils, buffering agents and surfactants.

Suitable formulations for administration by insufflation include finelycomminuted powders which may be delivered by means of an insufflator ortaken into the nasal cavity in the manner of a snuff. In theinsufflator, the powder is contained in capsules or cartridges,typically made of gelatin or plastic, which are either pierced or openedin situ and the powder delivered by air drawn through the device uponinhalation or by means of a manually-operated pump. The powder employedin the insufflator consists either solely of the active ingredient or ofa powder blend comprising the active ingredient, a suitable powderdiluent, such as lactose, and an optional surfactant. The activeingredient typically comprises from 0.1 to 100 w/w of the formulation.

In addition to the ingredients specifically mentioned above, theformulations of the present invention may include other agents known tothose skilled in the art of pharmacy, having regard for the type offormulation in issue. For example, formulations suitable for oraladministration may include flavoring agents and formulations suitablefor intranasal administration may include perfumes.

General Methods

General Methods

In one embodiment of this invention, the method for the preparation ofcompounds of Formulas I, II, I-A and II-A comprises the steps of:

(a) reacting an alcohol having the formula: L′-(CR⁴R⁵)_(n)-L, where L′and L are leaving groups, which may be the same or different, such as ahalogen (iodide, bromide or chloride), sulfonate (tosylate, mesylate,triflate, etc.) or is a group that is converted to a leaving group(e.g., an alcohol), with a compound having the formula:

where Y′ is —O—, —S—, or —NH— and X is defined as above or a protectedform thereof, to form a compound having the formula:

(b) forming a secondary amine by the reductive amination of an aldehyde

and a primary amine

to form

c) coupling the tertiary amine to the product of step a to form acompound having the formula:

(d) removing any protecting groups; and

(e) optionally derivitization of reactive functionality at X

The order of the steps can be changed such that a primary amine iscoupled to the product of step a prior to the reductive amination of theamide to the aldehyde, or the amine can be coupled to L′-(CR⁴R⁵)_(n)-Lprior to coupling to an appropriately derivitized ring, e.g.,

Further analogs prepared by alterations of X are detailed in theexperimental text.Specific Methods

Compounds of Formulas I, II, I-A and II-A of this invention where X isother than a heterocycle and Y is oxygen were prepared by methodsanalogous to those described in Scheme 1.

A phenolic nucleophile (2) displaced an alcohol (3), activated with apolymer-bound triphenyl phosphine and diisopropyl azodicarboxylate(DIAD) to give aryl ether (4). A secondary amine (7) was prepared byreductive amination of a primary amine (5) with an aldehyde (6) usingpolymer bound borohydride resin. The secondary amine (7) then displacedthe bromine from aryl-ether (4) to form a tertiary amine (8). The esterof this product was hydrolyzed under basic conditions to afford the freeacid (1). The hydrochloride salt of compound 1 was prepared, if desired,by adding HCl in ether.

Each of the above-described methods further include the optional step(s)of forming a pharmaceutically acceptable salt of a compound of thisinvention, and/or of forming a pharmaceutically acceptable solvate of acompound of this invention or a pharmaceutically acceptable saltthereof.

The following intermediates are useful in the methods described hereinto make the compounds of Formulas I, I-A, II and II-A:

-   {3-[4-(t-butyldimethylsilylhydroxy)but-1-ynyl]phenyl}acetic acid    methyl ester,-   {3-[4-hydroxybutyl]phenyl}acetic acid methyl ester,-   {3-[4-(toluene-4-sulfonyloxy)butyl]phenyl}acetic acid methyl ester,-   (S)-(2-chloro-3-trifluoromethyl-benzyl)-(2-phenyl-propyl)-amine,-   (R)-(2-chloro-3-trifluoromethyl-benzyl)-(2-phenyl-propyl)-amine,-   (2-chloro-3-trifluoromethyl-benzyl)-(naphthalene-1-ylmethyl)-amine,-   (2-chloro-3-trifluoromethyl-benzyl)-(phenethyl)-amine,-   (2-chloro-3-trifluoromethyl-benzyl)-(benzyl)-amine,-   (2-chloro-3-trifluoromethyl-benzylamino)-phenyl-ethanol,-   3-(3-benzyloxy-benzyl)-1,2,4-triazole,-   3-(3-benzyloxy-benzyl)-ethoxymethyl-1,2,4-triazole,-   [3-(ethoxymethyl)-1,2,4-triazol-3-ylmethyl]-phenol,-   {3-[3-(3-bromo-propoxy)-benzyl]}(ethoxymethyl)-1,2,4-triazole,-   (2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[3-(ethoxymethyl)-1,2,4-triazol-3-ylmethyl-phenoxy]-propyl}-amine,-   5-(3-benzyloxy-benzyl)-1,2,3,4-tetrazole,-   5-(3-benzyloxy-benzyl)-ethoxymethyl-1,2,3,4-tetrazole,-   5-(3-hydroxy-benzyl)ethoxymethyl-1,2,3,4-tetrazole,-   5-[3-(3-bromo-propoxy)-benzyl]-(ethoxymethyl)-1,2,3,4-tetrazole,-   (2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[3-(ethoxymethyl-1,2,3,4-tetrazol-5-ylmethyl)-phenoxy]-propyl}-amine,

and a stereoisomer, a stereoisomeric mixture or racemate thereof and apharmaceutically acceptable salt or solvate thereof.

The following Test Methods and Examples are intended for illustrationonly and are not intended to limit the scope of the invention in anyway; the present invention being defined by the claims.

In the Test Methods and Examples, the following terms have thedesignated meaning: “pRSETa” is a known expression vector available fromInvitrogen; “IPTG” means isopropyl β-D-thiogalactopyranoside; “PO₄”means phosphate; “PBS” means phosphate buffered saline; “TBS” meanstris-buffered saline; EDTA means ethylenediamine tetraacetic acid; “DTT”means dithiothreitol; “FAF-BSA” means fatty-acid free bovine serumalbumin; “SRC-1” means steroid receptor coactivator 1; “CS” meanscharcoal stripped; “nM” means nanomolar; “μM” means micromolar; “mM”means millimolar; “pM” means picomolar; “mmol” means millimoles; “g”means grams; “ng” means nanograms; “mg/ml” means milligram permilliliter; “μL” means microliters; and “mL” means milliliter.

Test Method 1: Ligand Sensing Assay (LiSA) for LXRβ Agonist Activity

This assay measures the recruitment of a peptide derived from thecoactivator protein, SRC1, to the agonist-bound LXRβ. Peptides derivedfrom other nuclear receptor cofactors may be similarly prepared andassayed.

To generate the human LXRβ ligand binding domain suitable for LiSA, amodified polyhistidine tag (MKKGHHHHHHG) (SEQ ID No. 1) was fused inframe to the human LXRβ ligand binding domain (amino acids 185-461 ofGenbank accession number U07132) and subcloned into the expressionvector pRSETa (Invitrogen) under the control of an IPTG inducible T7promoter. The human LXRβ ligand binding domain was expressed in E. colistrain BL21 (DE3). Ten-liter fermentation batches were grown in Rich PO₄media with 0.1 mg/mL Ampicillin at 25° C. for 12 hours, cooled to 9° C.and held at that temperature for 36 hours to a density of OD600=14. Atthis cell density, 0.25 mM IPTG was added and induction proceeded for 24hours at 9° C., to a final OD600=16. Cells were harvested bycentrifugation (20 minutes, 3500 g, 4° C.), and concentrated cellslurries were stored in PBS at −80° C.

Typically 25-50 g of cell paste is resuspended in 250-500 mL TBS, pH 8.0(25 mM Tris, 150 mM NaCl). Cells are lysed by passing 3 times through anAPV Rannie MINI-lab homogenizer and cell debris is removed bycentrifugation (30 minutes, 20,000 g, 4° C.). The cleared supernatant isfiltered through coarse pre-filters, and TBS, pH 8.0, containing 500 mMimidazole is added to obtain a final imidazole concentration of 50 mM.This lysate is loaded onto a column (XK-26, 10 cm) packed with Sepharose[Ni++ charged] Chelation resin (available from Pharmacia) andpre-equilibrated with TBS pH 8.0/50 mM imidazole. After washing tobaseline absorbance with equilibration buffer, the column is washed withapproximately one column volume of TBS pH −8.0 containing 95 mMimidazole. LXRβLBD(185-461) is eluted with a gradient from 50 to 500 mMimidazole. Column peak fractions are pooled immediately and diluted 5fold with 25 mM Tris pH 8.0, containing 5% 1,2-propanediol, 0.5 mM EDTAand 5 mM DTT. The diluted protein sample is then loaded onto a column(XK-16, 10 cm) packed with Poros HQ resin (anion exchange). Afterwashingto baseline absorbance with the dilution buffer the protein is elutedwith a gradient from 50-500 mM NaCl. Peak fractions are pooled andconcentrated using Centri-prep 10K (Amicon) filter devices and subjectedto size exclusion, using a column (XK-26, 90 cm) packed with Superdex-75resin (Pharmacia) pre-equilibrated with TBS, pH 8.0, containing 5%1,2-propanediol, 0.5 mM EDTA and 5 mM DTT.

LXRβ protein was diluted to approximately 10 μM in PBS and five-foldmolar excess of NHS-LC-Biotin (Pierce) was added in a minimal volume ofPBS. This solution was incubated with gentle mixing for 30 minutes atambient room temperature. The biotinylation modification reaction wasstopped by the addition of 2000× molar excess of Tris-HCl, pH 8. Themodified LXRβ protein was dialyzed against 4 buffer changes, each of atleast 50 volumes, PBS containing 5 mM DTT, 2 mM EDTA and 2% sucrose. Thebiotinylated LXRβ protein was subjected to mass spectrometric analysisto reveal the extent of modification by the biotinylation reagent. Ingeneral, approximately 95% of the protein had at least a single site ofbiotinylation; and the overall extent of biotinylation followed a normaldistribution of multiple sites, ranging from one to nine.

The biotinylated protein was incubated for 20-25 minutes at aconcentration of 5 nM in assay buffer (50 mM NaF, 50 mM MOPS-pH 7.5, 0.1mg/ml FAF-BSA, 0.05 mM CHAPS, 10 mM DTT) with equimolar amounts ofstreptavidin-AlloPhycoCyanin (APC, Molecular Probes). At the same time,the biotinylated peptide comprising amino acids 676-700 of SRC-1(CPSSHSSLTERHKILHRLLQEGSPS-CONH2) (SEQ ID No. 2) at a concentration of10 nM was incubated in assay buffer with a ½ molar amount ofstreptavidin-labelled Europium (Wallac) for 20-25 minutes. After theinitial incubations are completed, a 20 molar excess of biotin was addedto each of the solutions to block the unattached streptavidin reagents.After 20 min at room temp, the solutions were mixed yielding aconcentration of 5 nM for the dye-labeled LXR protein and 10 nM forSRC-1 peptide.

49 uL of the protein/peptide mixture was added to each well of an assayplate containing 1 ul of test compound serial diluted in 100% DMSO. Thefinal volume in each well was 0.05 mL, and the concentration in the wellfor the dye-labeled protein and peptide was 5 nM protein and 10 nMSRC1-peptide. The final test compound concentrations were between 33 pMand 20 uM. The plates were incubated at room temp 2-hours and thencounted on a Wallac Victor V fluorescent plate reader.

In this assay 1 μM 24(S), 25-epoxycholesterol gave a reading of 20000fluorescence units over a background reading of 10000 fluorescenceunits.

Test Method 2: Ligand Sensing Assay for LXRα Agonist Activity

The assay for LXRα was run according to the procedures of Test Method 1,above using his-tagged LXRα ligand binding domain (amino acids 183-447of Genbank accession number U22662, with the 14^(th) amino acidcorrected to A from R). In this assay 1 μM 24(S),25-epoxycholesterolgave a reading of 20000 fluorescence units over a background reading of10000 fluorescence units.

EXAMPLE 12-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2,2-dephenylethyl)amino]propoxy}phenyl)-ethanol

a) Methyl [3-(3-bromopropoxy)phenyl]acetate

A solution of methyl 3-hydroxyphenylacetate (11.3 g, 0.068 mole) in 300mL of anhydrous toluene was treated with 3-bromopropanol (12.2 g, 0.088mole). Polymer bound triphenylphosphine (36.0 g, 0.108 mole, 3 mmol/g,Fluka Chemie) was then added, and the mixture reacted for 15 minutes.The reaction mixture was then cooled to 0° C. anddiisopropylazodicarboxylate (16.9 g, 0.084 mol) was added in a dropwisefashion. After stirring at RT overnight, the crude reaction mixture wasfiltered and the solid washed with 100 mL toluene. After concentrationof the filtrate in vacuo, the crude product was purified by columnchromatography over silica gel (silica gel 60, EM Science) using 15%ethyl acetate:hexane as eluent to afford 15.8 g (81% yield) of the titlecompound as an oil: ¹H NMR (CDCl₃, 400 MHz) δ 7.23-7.19 (m, 1 H),6.85-6.7 (m, 3), 4.09-4.06 (t, 2 H, J=5.8), 3.67 (s, 3 H), 3.67-3.56 (m,4 H), 2.32-2.26 (p, 2 H, J=6.0); MS (ESI) 288 (MH⁺); TLC (hexanes:ethylacetate/3:1) R_(f)=0.68. Anal. (C₁₂H₁₅O₃Br) C, H, N.

b) [2-Chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amine

A solution of 2,2-diphenethylamine (10.0 g, 50.7 mmol) and2-chloro-3-trifluoromethylbenzaldehyde (10.5 g, 50.7 mmol) in 80 mL ofmethanol and 40 mL of trimethylorthoformate was stirred at RT for 15hours whereupon polymer-supported borohydride resin (20.3 g, 55.8 mmol,2.5 mmol/g, Aldrich) was added in one portion. After stirring at RT for24 h, the reaction was filtered and the filtrate was concentrated invacuo. The crude product was purified by column chromatography oversilica gel (silica gel 60, EM Science) using ethyl acetate:hexane/40:60with 1% NH₄OH as the eluent to give 11.2 g (57% yield) of the titlecompound as an oil: ¹H NMR (CDCl₃, 400 MHz) δ 7.57 (d, 1 H. J=8.0), 7.52(d, 1 H, J=7.6), 7.32-7.15 (m, 11 H), 4.20 (t, 1 H, J=7.6), 3.9 (s, 2H), 3.22 (d, 2 H, J=7.6); HPLC (Waters symmetry shield, RPq 3.5 micron,2.1×30 mm, 85:15/water acetonitrile with 0.1% HCOOH to 100% acetonitrileafter 4 min, flow rate=0.8 mL/min) t_(R)=2.39 min; MS (ESI) 390 (MH⁺);TLC (hexanes:ethyl acetate/4:1) R_(f)=0.42.

c) Methyl(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]propoxy}-phenyl)acetate

A solution of methyl [3-(3-bromopropoxy)phenyl]acetate (1.0 g, 3.48mmole) and [2-chloro-3-(trifluoromethyl)benzyl]-2,2-diphenylethylamine(1.63 g, 4.18 mmole) in 20 mL of acetonitrile was treated with potassiumcarbonate (0.72 g, 5.2 mmol). The reaction mixture was heated to refluxand stirred for 4 days. The reaction mixture was filtered, and thefiltrate was concentrated in vacuo. The crude product was purified byflash chromatography (silica gel cartridge, Biotage 32-63 um, 60A) with10% ethyl acetate:hexanes as the eluent to afford 1.69 g (81% yield) ofthe title compound as a viscous oil: ¹H NMR (CDCl₃, 400 MHz) δ 7.46-7.44(d, 1H, J=7.7), 7.25-7.14 (m, 12 H), 6.91-6.84 (m, 2 H), 6.666.62 (m, 2H) 4.154.09 (t, 1 H, J=7.6), 3.78 (s, 1 H), 3.69-3.66 (m, 5 H), 3.59 (S,2 H), 3.15-3.13 (d, 2 H, J=7.7), 2.72-2.68 (t, 2 H, J=6.6), 1.87-1.80(m, 2 H); MS (ESI) 597 (MH⁺); TLC (hexanes:Ethy acetate/9:1) R_(f)=0.36.

d)2-(33-[[2-Chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]propoxy}-phenyl)aceticacid hydrochloride salt

A solution of methyl(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]propoxy}phenyl)acetate(113 mg, 0.19 mmol) in 1.5 mL of tetrahydrofuran and 1 mL of water wastreated with 1N aqueous LiOH (0.29 mL, 0.29 mmol). After stirring at RTfor 2 hours, additional 1 N aqueous LiOH (0.29 mL, 0.29 mmol) was addedand stirring was continued for 2 hours. The reaction was neutralizedwith acetic acid (66 μL, 0.58 mmol) and poured into water/Ethyl acetate.The layers were separated and the aqueous layer was extracted with ethylacetate (3×). The combined organic layers were washed with brine (1×),dried over magnesium sulfate, filtered, and concentrated in vacuo. Thecrude material was purified by preparative thin layer chromatography(silica gel, 1 mm plates, Merck 20×20 cm silica gel 60 F₂₅₄) elutingwith methylene chloride:MeOH (95:5) to afford an oil. The oil wasdissolved in diethyl ether and acidified with excess HCl/diethyl ether.The reaction was concentrated in vacuo and dried under reduced pressureto give 65 mg (56% yield) of the title compound as a white solid: ¹H NMR(C₅D₅N, 400 MHz) δ 7.60-7.05 (m, 15 H), 7.01 (t, 1 H, J=7.6), 6.84 (dd,1 H, J=8.4, 2.4), 4.32 (t, 1 H, J=7.6), 3.89 (s, 2 H), 3.77 (s, 2 H),3.71 (t, 2 H, J=5.6), 3.16 (d, 2 H, J=7.6), 2.65 (t, 2 H, J=6.4),1.88-1.78 (m, 2 H).

e)2-(33-[[2-Chloro-3-(trifluoromethyl)benzyl](2,2-dephenylethyl)amino]propoxy}-phenyl)-ethanol

A solution of2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]propoxy}-phenyl)aceticacid hydrochloride (220 mg, 0.36 mmol) in THF (35 ml) at 0° C., wastreated with LiAlH₄ (1.0 ml of a 1N solution in THF), and the reactionwas stirred at 0° for 45 minutes. Ethyl acetate (10 ml) was added, thereaction warmed to RT, and water (20 ml) was added. The mixture wasextracted with ethyl acetate. The organic extracts were dried and thesolvent removed. The residue was chromatographed over silica gel(hexane/Ethyl acetate:3/7) to give a pure oil (42 mg, 20%). MS (ESI)568.0 (M+H)⁺.

EXAMPLE 22-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]propoxy}-phenyl)aceticacid, N-oxide

A solution of2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]propoxy}-phenyl)aceticacid hydrochloride from Example 1d (120 mg, 0.19 mmol) in acetic acid (3ml) was treated dropwise with H₂O₂ (1 ml, 30% solution), and thereaction stirred at RT for 16 hr, diluted with water and extracted withCHCl₃. The organic extracts were washed with water, dried andevaporated. The residue was crystallized from diethyl ether and gave apure solid (75 mg, 65%). MS (ESI) 598.0 (M+H)⁺.

EXAMPLE 3

(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]propoxy}-bromobenzene

a) 3-(3-Bromopropoxy)bromobenzene

Diethylazodicarboxylate (0.77 g, 3.8 mmol) was added to solution of3-bromophenol (0.50 g, 3.2 mmol), 3-bromopropanol (0.53 g, 3.8 mmol),triphenylphosphine (1.0 g, 3.8 mmol) and THF (10 mL). The solution wasmaintained at RT for 16 h and then concentrated in vacuo. The residuewas partitioned between methylene chloride and 10% NaHCO₃ aq. solutionand layers separated. The aqueous layer was extracted with methylenechloride (2×10 mL). The organic layers were combined, dried (MgSO₄) andconcentrated in vacuo. The crude product was purified by flash columnchromatography (100 g silica gel 60, 230-400 mesh, 9:1 hexane:ethylacetate as eluent) to give 0.63 g (71%) of the title compound as a paleyellow liquid. MS (ESI) 293.0 [M+H]⁺.

b)(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]propoxy}-bromobenzene

Potassium carbonate (140 mg, 1.0 mmol) and NaI (82 mg, 0.34 mmol) wereadded to a solution of 3-(3-bromopropoxy)bromobenzene (100 mg, 0.34mmol), (2-chloro-3-trifluoromethylbenzyl)(2,2-diphenylethyl)amine andacetonitrile (3 mL). The mixture was heated at reflux for 16 h. Themixture was allowed to cool to RT and concentrated in vacuo. The residuewas partitioned between methylene chloride and 10% NaHCO₃ aq. solutionand layers separated. The aqueous layer was extracted with methylenechloride (2×10 mL). The organic layers were combined, dried (MgSO₄) andconcentrated in vacuo. The residue was purified by preparative HPLC (YMCCombiPrep ODS-A, 50×20 mm, 20 mL/min, A: 0.1% trifluoroacetic acid inacetonitrile B: 0.1% aqueous trifluoroacetic acid, A: 10 to 90% during10 min, UV detection at 254 nm) to give 52 mg (29%) of the titlecompound as an oil. MS (ESI) 639.2 [M+H]⁺.

EXAMPLE 4(4-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]propoxy}-bromobenzene

Following the procedure of Example 3, except substituting4-(3-bromopropoxy)bromobenzene for 3-(3-bromopropoxy)bromobenzene gavethe title compound as an oil (23%). MS (ESI) 638.6 [M+H]⁺.

EXAMPLE 5(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenylethyl)-{3-[3-(1,2,4-triazol-3-ylmethyl)-phenoxy]-propyl)aminehydrochloride salt

a) 3-(3-Benzyloxy-benzyl)-1,2,4-triazole

To a stirring solution of 3-benzyloxyphenylacetonitrile (5.0 g, 0.022mole) in methanol (100 mL) was added formic hydrazide (2.69 g, 0.060mole) and solid potassium carbonate (9.9 g, 0.027 mole). The reactionwas heated at reflux and stirred overnight. The mixture was cooled toRT, filtered, and the filtrate was concentrated. The crude product waspurified by column chromatography over silica gel (silica gel 60, EMScience) using 75% ethyl acetate:hexane as eluent to afford 1.8 g (30%yield) of the title compound as an oil: MS (ESI) 266.0 (M+H⁺).

b) 3-(3-Benzyloxy-benzyl)-ethoxymethyl-1,2,4-triazole

(Mixture of Regioisomers for Ethoxymethyl Include 1-, 2-, and 4-)

To a stirring solution of 3-(3-benzyloxy-benzyl)-1,2,4-triazole (1.0 g,0.0037 mole) in DMF (20 mL) at 0° C. was added NaH (0.195 g, 0.0049mole) and the mixture was stirred for 20 min. To this mixture was addedchloromethyl ethyl ether (0.354 g, 0.0037 mole), and the mixture waswarmed to RT and stirred overnight. The reaction mixture was poured intowater (100 mL) and extracted three times with ethyl acetate. The ethylacetate extracts were dried over Na₂SO₄, filtered, and concentrated. Thecrude product was purified by column chromatography over silica gel(silica gel 60, EM Science) using 60% ethyl acetate:hexane as eluent toafford 1.0 g (89% yield) of the title compounds as an oil: MS (ESI)324.0 (M+H⁺).

c) [3-(Ethoxymethyl)-1,2,4-triazol-3-ylmethyl]-phenol

(Mixture of Regioisomers for Ethoxymethyl Include 1-, 2-, and 4-)

To a stirring solution of3-(3-Benzyloxy-benzyl)-ethoxymethyl-1,2,4-triazole (mixture ofregioisomers, 1.0 g, 0.0031 mole) in methanol (20 mL) was addedpalladium on carbon (0.1 g, 10 wt. %). The reaction mixture was stirredat RT under an H₂ atmosphere overnight. The crude reaction mixture wasfiltered, and the filtrate was concentrated in vacuo to give 0.75 g (99%yield) of title compounds as an oil. MS(ESI) 234.0 (M+H⁺).

d) {3-[3-(3-Bromo-propoxy)-benzyl]}-(ethoxymethyl)-1,2,4-triazole

(Mixture of Regioisomers for Ethoxymethyl Include 1-, 2-, and 4-)

A solution of [3-(ethoxymethyl)-1,2,4-triazol-3-ylmethyl]-phenol(mixture of regioisomers, 300 mg, 1.27 mmol) in anhydrous toluene (10mL) was treated with 3-bromo propanol (230 mg, 1.66 mmol). Polymer boundtriphenylphosphine (680 mg, 2.04 mmol, 3 mmol/g, Fluka Chemie) was thenadded, and the mixture was stirred for 15 minutes. The reaction mixturewas then cooled to, 0° C. and diisopropylazodicarboxylate (320 mg, 1.58mmol) was added in a dropwise fashion. The reaction mixture was stirredat RT overnight, the crude reaction mixture was filtered, and thefiltrate was concentrated in vacuo to give 400 mg (88% yield) of titlecompounds as an oil. MS(ESI) 356.0 (M+2H⁺).

e) (2,2-Diphenylethyl)(2-chloro-3-trifluoromethyl-benzyl)amine

To a stirring solution of 2,2-diphenethylamine (2.0 g, 0.010 mole) and2-chloro-3-trifluoromethylbenzaldehyde (2.33 g, 0.011 mole) indichloromethane (20 mL) was added sodium triacetoxyborohydride (2.36° g,0.011 mole) and acetic acid (2.0 mL). The reaction mixture was stirredovernight. The solvent was removed and the residue was dissolved inethyl acetate. The ethyl acetate solution was washed with saturatedNaHCO₃, the ethyl acetate extracts were dried over Na₂SO₄, filtered, andconcentrated. The crude product was subjected to column chromatographyover silica gel (silica gel 60, EM Science) using 30% ethylacetate:hexane as eluent to afford 3.0 g (76% yield) of the titlecompound as a yellow oil: MS (ESI) 390.0 (M+H⁺).

f)(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[3-(ethoxymethyl)-1,2,4-triazol-3-ylmethyl-phenoxy]-propyl}-amine

(Mixture of Regioisomers for Ethoxymethyl Include 1-, 2-, and 4-)

A solution of{3-[3-(3-bromo-propoxy)-benzyl]}(ethoxymethyl)-1,2,4-triazole (mixtureof regioisomers, 150 mg, 0.421 mmol) and(2,2-diphenylethyl)-(2-chloro-3-trifluoromethyl)amine (164 mg, 0.421mmol) in acetonitrile (5 ml) was treated with solid potassium carbonate(175 mg, 1.26 mmol) and NaI (189 mg, 1.26 mmol). The reaction mixturewas heated to reflux and stirred overnight. The mixture was cooled toRT, filtered, and the filtrate was concentrated. The crude product waspurified by preparative HPLC (YMC CombiPrep PDS, 75×30 mm, 25 mL/min, A:acetonitrile B: water, A: 80 to 100% during 10 min, UV detection at 254nm) to give 98 mg (35% yield) of title compound as a viscous oil. MS(ESI) 663.2 (M⁺).

g)(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenyl-ethyl)-{3-[3-(1,2,4-triazol-3-ylmethyl)-phenoxy]-propyl}-aminehydrochloride salt

To a stirring solution of(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[3-(ethoxymethyl-1,2,4-triazol-3-ylmethyl)-phenoxy]-propyl)amine(mixture of regioisomers, 90 mg, 0.135 mmol) in dichloromethane (1.5 mL)was added triethylsilane (157 mg, 1.35 mmol). The reaction mixture wastreated with TFA (0.5 mL) and then stirred overnight Solvent was removedand the residue was purified by preparative HPLC (YMC CombiPrep PDS,75×30 mm, 25 mL/min, A: acetonitrile B: water, A: 60 to 100% during 10min, UV detection at 254 nm) to give an oil. The oil was dissolved indiethyl ether and acidified with 1.0 M HCl/diethyl ether to give 40 mg(48% yield) of the title compound as a yellow oil. MS (ESI) 605.0 (M⁺).

EXAMPLE 6(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[3-(1,2,3,4-tetrazol-5-ylmethyl)-phenoxy]-propyl}-amine

a) 5-(3-Benzyloxy-benzyl)-1,2,3,4-tetrazole

To a stirring solution of 3-benzyloxyphenylacetonitrile (2.0 g, 8.95mmol) in toluene (17 ml) was added trimethylsilylazide (2.37 g, 17.9mmol) and di-n-butyltin oxide (0.22 g, 0.9 mmol). The mixture was heatedat 110° C. for 48 h, and was concentrated. The reaction mixture wasdissolved in ethyl acetate (100 ml) and washed two times with 10%aqueous sodium bicarbonate. The basic extracts were acidified to pH<2with conc. HCl, and the aqueous layer was extracted with ethyl acetate.The combined organic layers were dried over sodium sulfate, filtered,and concentrated. The crude product (2.0 g, 89%) was used in the nextstep without further purification. MS (ESI) 267.0 (M+H⁺).

b) 5-(3-Benzyloxy-benzyl)-ethoxymethyl-1,2,3,4-tetrazole

(Mixture of Regioisomers for Ethoxymethyl Include 1- and 2-)

To a stirring solution of 3-(3-benzyloxy-benzyl)-1,2,3,4-tetrazole (2.12g, 7.96 mmol) in DMF (40 ml) at 0° C. was added NaH (0.38 g, 9.55 mmol).To this mixture was added chloromethyl ethyl ether (0.81 ml, 8.75 mmol),and the solution was stirred at RT overnight. The reaction mixture waspoured into water (120 ml) and extracted three times with ethyl acetate.The ethyl acetate extracts were dried over Na₂SO₄, filtered, andconcentrated. The crude mixture was subjected to column chromatography(silica gel, ethyl acetate/hexane) to provide the title compounds as amixture of regioisomers as a light yellow oil (1.39 g, 55%). MS (ESI)324.8 (M+).

c) 5-(3-Hydroxy-benzyl)-ethoxymethyl-1,2,3,4-tetrazole

(Mixture of Regioisomers for Ethoxymethyl Include 1- and 2-)

To a stirring solution of5-(3-benzyloxy-benzyl)-ethoxymethyl-1,2,3,4-tetrazole (mixture ofregioisomers, 0.23 g, 0.71 mmol) in MeOH (5 ml) was added palladium oncarbon (20 mg). The mixture was stirred for 7 h under H₂ atmosphere,filtered, and concentrated. The crude phenol was purified by preparativeHPLC (YMC CombiPrep PDS, 75×30 mm, 25 mL/min, acetonitrile:H₂O, UVdetection at 254 nm) to afford the desired phenol as a clear oil (0.14g, 84%). MS (ESI) 235.0 (M+H⁺).

d) 5-[3-(3-Bromo-propoxy)-benzyl]-(ethoxymethyl)-1,2,3,4-tetrazole

(Mixture of Regioisomers for Ethoxymethyl Include 1- and 2-)

A solution of 5-(3-hydroxy-benzyl)-ethoxymethyl-1,2,3,4-tetrazole(mixture of regioisomers, 132 mg, 0.56 mmol) in anhydrous toluene (5 ml)was treated with 3-bromo-propanol (117 mg, 0.84 mmol). Polymer boundtriphenylphosphine (0.56 mg, 1.7 mmol, 3 mmol/g, Fluka Chemie) was thenadded, and the mixture stirred for 15 minutes. The reaction mixture wasthen cooled to 0° C. and diisopropylazodicarboxylate (166 ul, 0.84 mmol)was added dropwise. The reaction mixture was stirred at RT overnight,filtered, and the filtrate was concentrated in vacuo to give 200 mg(100% yield) of a 1:1 mixture of the title compounds as a yellow oil. MS(ESI) 356.8 (M+2H⁺).

e)(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[3-(ethoxymethyl-1,2,3,4-tetrazol-5-ylmethyl)-phenoxy]-propyl}-amine

(Mixture of Regioisomers for Ethoxymethyl Include 1- and 2-)

A solution of(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[3-(ethoxymethyl-1,2,3,4-tetrazol-5-ylmethyl)-phenoxy]-propyl}-amine(mixture of regioisomers, 0.2 g, 0.56 mmol) and(2,2-diphenylethyl)-(2-chloro-3-trifluoromethyl)amine (0.43 g, 1.12mmol) in acetonitrile (10 ml) was treated with solid potassium carbonate(0.23 g, 1.7 mmol) and NaI (0.25 g, 1.7 mmol). The reaction was heatedat reflux and stirred overnight. The mixture was cooled to RT, filtered,and concentrated. The crude product was purified by preparative HPLC(YMC CombiPrep PDS, 75×30 mm, 25 mL/min, acetonitrile: water, UVdetection at 254 nm) to give 125 mg (33% yield) of the title compound asa viscous oil. MS (ESI) 664.2 (M⁺).

f)(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[3-(1,2,3,4-tetrazol-5-ylmethyl)-phenoxy]-propyl}-amine

To a stirring solution of(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[3-(ethoxymethyl-1,2,3,4-tetrazol-5-ylmethyl)-phenoxy]-propyl}-amine(mixture of regioisomers, 125 mg, 0.19 mmol) in dichloromethane (11 ml)was added triethylsilane (116 mg, 1.08 mmol). The reaction mixture wastreated with TFA (3 ml) and then stirred overnight. Solvent was removedand the residue was purified by preparative HPLC (YMC CombiPrep PDS,75×30 mm, 25 mL/min, acetonitrile:water, UV detection at 254 nm) toafford 50 mg (44%) the title compound as a yellow oil. MS (ESI)607.0(M+H⁺).

EXAMPLE 7(2-Chloro-3-trifluoromethyl-benzyl)-(2-cyclohexyl-2-phenyl-ethyl)-{3-[3-(1,2,3,4-tetrazol-5-ylmethyl)-phenoxy]-propyl)amine

a) 2-Cyclohexyl-2-phenyl-acetic acid Methyl ester

To a stirring solution of 2-cyclohexyl-2-phenyl-acetic acid (2 g, 0.0091mole) in methanol (100 mL) was added HCl (2 mL), and the mixture washeated at reflux for 5 hours. Methanol was removed, the residue wasdissolved in ethyl acetate, and washed with saturated NaHCO₃. Theorganic layer was dried over sodium sulfate, filtered, and concentratedin vacuo to give 2.2 g (99% yield) of the title compound as an oil. MS(ESI) 233.2 (M+H⁺).

b) 2-Cyclohexyl-2-phenyl-ethanol

To a stirring solution of 2-cyclohexyl-2-phenyl-acetic acid methyl ester(2.2 g, 0.0094 mole) in THF (20 mL) was added 19 mL of a lithiumaluminum hydride solution (1.0 M in THF) at 0° C. The reaction mixturewas stirred overnight and 10% KOH (8 mL) was added. The mixture wasfiltered, and then washed with ether. Ether (60 mL) was added to thefiltrate and the ethereal solution was washed with water (50 mL). Theether layer was dried over sodium sulfate, filtered, and concentrated togive 1.86 g (97% yield) of the title compound as an oil. 1H-NMR (400MHz, CDCl₃) δ 7.37-7.15 (m, 5H), 3.97 (t, 1H, J=6.0 Hz), 3.86 (t, 1H,J=9.0 Hz), 2.59 (q, 1H, J=4.0 Hz), 1.96-1.03 (m, 11H). The primaryalcohol was used without further purification.

c) (2-Azido-1-cyclohexyl-ethyl)-benzene

To a stirring solution of 2-cyclohexyl-2-phenyl-ethanol (0.9 g, 0.00441mole) and triethylamine (0.536 g, 0.0053 mole) in dichloromethane (10mL) at 0° C. was added methanesulfonyl chloride (0.606 g, 0.0053 mole).The reaction was stirred at RT for 2 h. The reaction mixture was nextpoured into water, and extracted three times with dichloromethane. Thesolvent was removed and DMF (10 mL) was added to the residue. NaN₃ (0.57g, 0.0088 mole) was added to the solution and the mixture was thenstirred overnight at RT. The reaction mixture was washed with water andextracted three times with ethyl acetate. The combined organic layerswere dried over sodium sulfate, filtered, and concentrated. The crudeproduct was purified by column chromatography over silica gel (silicagel 60, EM Science) using 20% ethyl acetate:hexane as eluent to afford0.79 g (78% yield) of the title compound as an oil. 1H-NMR (400 MHz,CDCl₃) δ 7.26-7.08 (m, 5H), 3.58 (dd, 1H, J=5.2 Hz), 3.48 (dd, 1H, J=8.8Hz), 2.53 (q, 1H. J=5.2 Hz), 1.87-0.7 (m, 11H).

d) 2-Cyclohexyl-2-phenyl-ethylamine

To a stirring solution of (2-azido-1-cyclohexyl-ethyl)-benzene (700 mg,3.06 mmol) in methanol (20 mL) was added palladium on carbon (70 mg, 10wt. %). The mixture was stirred at 50 Psi H₂ overnight, filtered, andwashed with methanol, and the filtrate was concentrated in vacuo to give650 mg (99% yield) of title compound as an oil. 1 H-NMR (400 MHz, CDCl₃)δ 7.34-7.16 (m, 5H), 3.13 (t, 1H, J=4.5 Hz), 2.92 (t, 1H, J=2.3 Hz),2.40 (m, 1H), 1.73-0.74 (m, 11H).

e)(2-Cyclohexyl-2-phenyl-ethyl)-(2-chloro-3-trifluoromethyl-benzyl)-amine

Following the procedure in Example 5(e) except2-cyclohexyl-2-phenyl-ethylamine was used instead of2,2-diphenethylamine, the title compound was isolated to give 630 mg ofa white solid (50% yield). MS (ESI) 396.4 (M+H⁺).

f)(2-Chloro-3-trifluoromethyl-benzyl)-(2-cyclohexyl-2-phenyl-ethyl)-{3-[3-(ethoxymethyl-1,2,3,4-tetrazol-3-ylmethyl)-phenoxy]-propyl}-amine

(Mixture of 1- and 2-ethoxymethyl-tetrazolyl Regioisomers),

Following the procedure of Example 6(a)-(f) except(2-cyclohexyl-2-phenyl-ethyl)-(2-chloro-3-trifluoromethyl-benzyl)-aminewas used in step e instead of(2,2-diphenylethyl)-(2-chloro-3-trifluoromethyl-benzyl)amine, the titlecompound was isolated to afford 320 mg of an oil (42%). MS (ESI) 670.2(M⁺).

g)(2-Chloro-3-trifluoromethyl-benzyl)-(2-cyclohexyl-2-phenyl-ethyl)-{3-[3-(1,2,3,4-tetrazol-3-ylmethyl)-phenoxy]-propyl}-amine

A solution of(2-chloro-3-trifluoromethyl-benzyl)-(2-cyclohexyl-2-phenyl-ethyl)-{3-[3-(½-ethoxymethyl-1,2,3,4-tetrazol-3-ylmethyl)-phenoxy]-propyl}-amine(140 mg, 0.209 mmol) in dichloromethane (2 ml) was added triethylsilane(243 mg, 2.09 mmol). The reaction mixture was treated with TFA (0.6 ml)and then stirred overnight. The crude product was purified by columnchromatography over silica gel (silica gel 60, EM Science) using 75%ethyl acetate:hexane as eluent to afford 65 mg (51% yield) of the titlecompound as an oil: MS (ESI) 612.0 (M⁺).

EXAMPLE 8(S)-(2-Chloro-3-trifluoromethyl-benzyl)-(2-phenyl-propyl)-{3-[3-(1,2,3,4-tetrazol-3-ylmethyl)-phenoxy]-propyl}-aminehydrochloride salt

a) (S)-(2-Chloro-3-trifluoromethyl-benzyl)-(2-phenyl-propyl)-amine

Following the procedure of Example 5e except (S)-2-phenyl-propylaminewas used instead of 2,2-diphenethylamine, the title compound wasisolated to give a white solid (60%). MS (ESI) 328.0 (M+H⁺).

b)(S)-(2-Chloro-3-trifluoromethyl-benzyl)-(2-phenyl-propyl)-{3-[3-(1,2,3,4-tetrazol-3-ylmethyl)-phenoxy]-propyl}-aminehydrochloride salt

Following the procedure of Example 6(a-f) except(S)-(2-chloro-3-trifluoromethyl-benzyl)-(2-phenyl-propyl)-amine was usedinstead of (2,2-diphenylethyl)-(2-chloro-3-trifluoromethyl)-amine instep e, the title compound was synthesized. The resulting tertiary aminewas dissolved in diethyl ether and acidified with 1.0 M HCl/diethylether. The reaction mixture was concentrated and dried under reducedpressure to give 59 mg (5% overall yield) of the title compound as awhite solid. MS (ESI) 544.0 (M⁺).

EXAMPLE 9(R)-(2-Chloro-3-trifluoromethyl-benzyl)-(2-phenyl-propyl)-{3-[3-(1,2,3,4-tetrazol-3-ylmethyl)-phenoxy]-propyl}-aminehydrochloride salt

a) (R)-(2-Chloro-3-trifluoromethyl-benzyl)-(2-phenyl-propyl)-amine

Following the procedure of Example 5e except (R)-2-phenyl-propylaminewas used instead of 2,2-diphenethylamine, the title compound wasisolated to give a white solid (62%). MS (ESI) 328.0 (M+H⁺).

b)(R)-(2-Chloro-3-trifluoromethyl-benzyl)-(2-phenyl-propyl)-{3-[3-(1,2,3,4-tetrazol-5-ylmethyl)-phenoxy]-propyl}-aminehydrochloride salt

Following the procedure of Example 6(a-f) except(R)-(2-chloro-3-trifluoromethyl-benzyl)-(2-phenyl-propyl)-amine was usedinstead of (2,2-diphenylethyl)-(2-chloro-3-trifluoromethyl)-amine instep e, the title compound was synthesized. The resulting amine wasdissolved in diethyl ether and acidified with 1.0 M HCl/diethyl ether.The reaction mixture was concentrated and dried under reduced pressureto give 60 mg (10% overall yield) of the title compound as a whitesolid. MS (ESI) 544.0 (M⁺).

EXAMPLE 10(S)-2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2-phenyl-propyl)amino]propoxy}-phenyl)aceticacid hydrochloride salt

a) (S)-(2-Chloro-3-trifluoromethyl-benzyl)-(2-phenyl-propyl)-amine

To a solution of (S)-2-phenyl propylamine (0.5 g, 3.7 mmol) in drydichloromethane was added acetic acid followed by2-chloro-3-trifluoromethylbenzaldehyde (1.1 g, 5.5 mmol) and sodiumtriacetoxyborohydride (1.5 g, 7.4 mmol). After the resulting mixture wasstirred for 1.5 h at RT water was added to quench the reaction. Theaqueous layer was extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over sodium sulfate, andconcentrated in vacuo. The crude mixture was purified by columnchromatograph (Ethyl acetate:Hexane/25:75) to give the title compound asan oil (0.55 g, 45%). MS (ESI) 327.6 (M+H)⁺.

b)(S)-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2-phenyl-propyl)amino]propoxy}-phenyl)aceticacid methyl ester

A solution of (3-{3-bromo-propoxy}-phenyl)acetic acid methyl ester (0.55g, 1.5 mmol) and(S)-(2-Chloro-3-trifluoromethyl-benzyl)-(2-phenyl-propyl)-amine (0.55 g,1.6 mmol) in acetonitrile (10 ml) was treated with solid potassiumcarbonate(0.4 g, 2.4 mmol). The reaction was heated to reflux andstirred for 48 h. Upon cooling to RT, the reaction was filtered througha pad of celite, washed with ethyl acetate, and the filtrate wasconcentrated in vacuo. The crude product was purified by columnchromatograph (Ethyl acetate:Hexane/20:80) to give the title compound asan oil (0.6 g, 67%). MS (ESI) 534.6 (M+H)⁺.

c)(S)-2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2-phenyl-propyl)amino]propoxy}-phenyl)aceticacid

A solution of(S)-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2-phenyl-propyl)amino]propoxy}-phenyl)aceticacid methyl ester (0.6 g, 1.1 mmol) in THF (9 ml) and water (6 ml) wastreated with aqueous LiOH (1.0 N, 1.0 ml, 1.0 mmol). After stirring atRT for 2 h, additional LiOH (1.0 ml, 11.0 mmol) was added and stirringwas continued for 2 h. The reaction was neutralized with acetic acid andpoured into water and ethyl acetate. The layers were separated and theaqueous layer was extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over sodium sulfate andconcentrated in vacuo. The crude mixture was purified by HPLC to givethe title compound as an oil (0.4 g, 75%). MS (ESI) 520.2 (M+H)⁺.

d)(S)-2-(3-{3-[[2-Chloro-3-trifluoromethyl)benzyl](2-phenyl-propyl)amino]propoxy}-phenyl)aceticacid hydrochloride salt

To a solution of the(S)-2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2-phenyl-propyl)amino]propoxy}-phenyl)aceticacid in ethyl ether was added HCl in diethyl ether (1.0M). Thesuspension was filtered and dried to give the title compound as a whitesolid (99%). NMR(400 MHz, CD₃OD) δ: 8.0 (d, J=4.0 Hz, 1H), 7.9 (d, J=4.0Hz, 1H), 7.7-7.3 (m, 7H), 7.1 (d, J=8.0 Hz, 1H), 6.8 (m, 2H), 4.1-3.4(m, 11H), 2.3 (m, 2H), 1.5 (d, J=4.0 Hz, 3H).

EXAMPLE 11(R)-2-(3-{3-[[2-Chloro-3-trifluoromethyl)benzyl](2-phenyl-propyl)amino]propoxy}-phenyl)aceticacid hydrochloride salt

Following the procedure of Example 10 (a-d) except substituting(R)-2-phenyl propylamine for (S)-2-phenyl propylamine in step a, thetitle compound was obtained as a white solid (0.3 g, 80%). MS (ESI)520.2 (M+H)⁺. NMR (400 MHz, CD₃OD) δ: 8.0 (d, J=4.0 Hz, 1H), 7.9 (d,J=4.0 Hz, 1H), 7.7-7.3 (m, 7H), 7.1 (d, J=8.0 Hz, 1H), 6.8 (m, 2H),4.1-3.4 (m, 11H), 2.3 (m, 2H), 1.5 (d, J=4.0 Hz, 3H).

EXAMPLE 122-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl]naphthalen-1-ylmethyl-amino]propoxy}-phenyl)aceticacid hydrochloride salt

Following the procedure of Example 10 (a-d) except substituting1-naphthalenemethylamine for (S)-2-phenyl propylamine in step a, thetitle compound was obtained as a white solid (80%).

EXAMPLE 132-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl]-benzylamino]propoxy}-phenyl)aceticacid hydrochloride salt

Following the procedure of Example 10 (a-d) except substitutingbenzylamine for (S)-2-phenyl propylamine in step a, the title compoundwas obtained as a white solid (80%). MS (ESI) 492.2 (M+H)⁺.

EXAMPLE 142-(3-{3-[[2-Chloro-3-(trifluoromethyl)-benzyl]phenethylamino]propoxy}-phenyl)aceticacid hydrochloride salt

Following the procedure of Example 10 (a-d) except substitutingphenethylamine for (S)-2-phenyl propylamine in step a, the titlecompound was obtained as a white solid (80%). MS (ESI) 506.2 (M+H)⁺.

EXAMPLE 152-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2-hydroxy-2-phenyl-ethyl)amino]propoxy}-phenyl)aceticacid hydrochloride salt

a)2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2-hydroxy-2-phenyl-ethyl)amino]propoxy}-phenyl)aceticacid methyl ester

Following the procedure of Example 10 (a-b), except substituting2-amino-1-phenylethanol for (S)-2-phenyl propylamine for in step a, thetitle compound was obtained as an oil. (80%) MS (ESI) 536.0 (M+H)⁺

b)2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2-hydroxy-2-phenyl-ethyl)amino]propoxy}-phenyl)aceticacid

Following the procedure of Example 10 (c), the title compound wasobtained as an oil. (65%) MS (ESI) 522.2 (M+H)⁺

c)2-(3-{3-[[2-Chloro-3-trifluoromethyl)benzyl](2-hydroxy-2-phenyl-ethyl)amino]propoxy}-phenyl)aceticacid hydrochloride salt

Following the procedure of Example 10 (d), the title compound wasobtained as a white solid (99%). MS (ESI) 522.2 (M+H)⁺.

EXAMPLE 162-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2-acetoxy-2-phenyl-ethyl)amino]propoxy}-phenyl)aceticacid hydrochloride salt

a)2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2-acetoxy-2-phenyl-ethyl)amino]propoxy}-phenyl)aceticacid

A solution of2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2-hydroxy-2-phenyl-ethyl)amino]propoxy}-phenyl)aceticacid (Example 15 b) in anhydrous toluene (5 ml) was treated with aceticacid (3 mg). Polymer bound triphenylphosphine (30 mg, 3 mmol/g) was thenadded, and the mixture reacted for 15 min. The reaction mixture was thencooled to 0° C. and diisopropylazodicarboxylate(10 mg, 0.05 mmol) wasadded dropwise. After stirring at RT overnight the crude mixture wasfiltered and the solid washed with 10 ml toluene. After concentration ofthe filtrate in vacuo, the crude product was purified by HPLC to givethe title compound as an oil (20 mg, 75%). MS (ESI) 563.8 (M+H)⁺.

b)2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2-acetoxy-2-phenyl-ethyl)amino]propoxy}-phenyl)aceticacid hydrochloride salt

To a solution of2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2-acetoxy-2-phenyl-ethyl)amino]propoxy}-phenyl)aceticacid in ethyl ether was added HCl in diethyl ether (1.0M). Thesuspension was filtered and dried to give the title compound as a whitesolid (99%). NMR(400 MHz, CD₃OD) δ: 7.8 (m, 3H), 7.3 (s, 5H), 7.1 (t,J=4.0 Hz, 1H), 6.7 (m, 3H), 6.1 (m, 1H), 4.0 (m, 2H), 3.6-3.4 (m, 7H),2.2 (m, 2H), 1.9 (s, 3H), 1.1 (t, J=4.2 Hz, 2H).

EXAMPLE 172-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2-phenoxy-2-phenyl-ethyl)amino]propoxy}-phenyl)aceticacid hydrochloride salt

Following the procedure of Example 16 (a-b), except substituting phenolfor acetic acid in step a, the title compound was obtained as a whitesolid (80%). MS (ESI) 597.8 (M+H)⁺.

EXAMPLE 18 Benzoic acid2-[3-(3-carboxymethyl-phenoxy){2-chloro-3-(trifluoromethyl)benzyl}propylamino]-1-phenylethyl ester hydrochloride salt

Following the procedure of Example 16 (a-b), except substituting benzoicacid for acetic acid in step a, the title compound was obtained as awhite solid (80%). MS (ESI) 626.2 (M+H)⁺.

EXAMPLE 19(3-{3-[(2-Acetoxy-2-phenyl-ethyl)-(2-chloro-3-trifluoromethyl-benzyl)-amino]-propoxy}phenyl)-aceticacid methyl ester

Following the procedure of Example 16 (a) using2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2-hydroxy-2-phenyl-ethyl)amino]propoxy}-phenyl)aceticacid methyl ester (Example 15a), the title compound was yielded as awhite solid (80%) MS (ESI) 578.0 (M+H)⁺

EXAMPLE 20 Benzoic acid2-[3-(3-methoxycarbonylmethyl-phenoxy){2-chloro-3-(trifluoromethyl)benzyl}propylamino]-1-phenylethyl ester

Following the procedure of Example 16 (a), except substituting benzoicacid for acetic acid, and using2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2-hydroxy-2-phenyl-ethyl)amino]propoxy}-phenyl)aceticacid methyl ester (Example 15a) as the substrate, the title compound wasobtained as a white solid (80%) MS (ESI) 639.4 (M+H)⁺.

EXAMPLE 21(3-{4-[(2-Chloro-3-(trifluoromethyl)benzyl)-(2,2-diphenylethyl)-amino]butyl}phenyl)-aceticacid

a) 1-(t-Butyldimethylsilyloxy)but-3-yne

A solution of 1-hydroxybut-3-yne (2.0 g, 0.028 mol) and imidazole (2.9g, 0.043 mol) in DMF (5 ml) was treated with t-butyldimethylsilylchloride (6.4 g, 0.043 mol). After 24 hr. at RT, the reaction wasdiluted with water and extracted with diethyl ether. The organicextracts were washed with water, dried, evaporated, and the volatileorganics were removed by vacuum to afford the title compound as an oil(4.6 g, 89%). ¹H NMR (400 MHz, CDCl3): δ 3.67 (t, J=7.1 Hz, 2H), 2.32(m, 2H), 1.88 (s, 1H), 0.82 (s, 9H), 0.00 (s, 6H).

b) {3-[4-(t-Butyldimethylsilylhydroxy)but-1-ynyl]phenyl}acetic acidmethyl ester

A mixture of (3-iodo-phenyl)-acetic acid methyl ester (948 mg, 3.4mmol), 1-(t-butyldimethylsilyloxy)but-3-yne (644 mg, 3.5 mmol),copper(1)iodide (50 mg), andbis(triphenylphosphine)-palladium(II)chloride (50 mg) in Et₃N (5 ml) wasrefluxed, under argon for 2 hr. The reaction was cooled, and the liquidwas decanted off, diluted with diethyl ether, and washed with 1N HCl.The organic layer was dried and the solvent was evaporated. The residuewas chromatographed on silica gel (hexane/methylene chloride 60/40) togive the title compound as an oil (700 mg, 62%). MS (ESI) 333.0 (M+H)⁺.

c) {3-[4-Hydroxybutyl]phenyl}acetic acid methyl ester

A solution of {3-[4-(t-butyidimethylsilyloxy)but-1-ynyl]phenyl}aceticacid methyl ester (700 mg, 2.1 mmol) in MeOH (15 ml) was treated with 5%Pd/C (100 mg) and hydrogen gas (1 atm) for 1 hr. The catalyst wasfiltered, and the solvent evaporated. The residue was dissolved in THF(1 ml), and treated with tetrabutyl ammonium fluoride (2 ml of a 1Nsolution in THF) for 2 hr. The reaction was diluted with water andextracted with diethyl ether. The organic extracts were washed withwater, dried, evaporated, and the volatile organics removed by vacuum togive the title compound as an oil (300 mg, 64%). MS (ESI) 223.2 (M+H)⁺.

d) {3-[4-(Toluene-4-sulfonyloxy)butyl]phenyl}acetic acid methyl ester

A solution of {3-[4-hydroxybutyl]phenyl)acetic acid methyl ester (300mg, 1.35 mmol) and p-toluenesulfonyl chloride (513 mg, 2.7 mmol) inpyridine (5 ml) was stirred at RT for 18 hr. The reaction was dilutedwith water (50 ml) and extracted with diethyl ether. The organicextracts were washed with water and cold 1N HCl, dried, and the solventevaporated to give the title compound as an oil (322 mg, 63%). MS (ESI)377.3 (M+H)⁺.

e)(3-{4-[(2-Chloro-3-trifluoromethyl)benzyl)-(2,2-diphenylethyl)-amino]butyl}phenyl)-aceticacid methyl ester

A mixture of {3-[4-(toluene-4-sulfonyloxy)butyl]phenyl}acetic acidmethyl ester,(2,2-diphenylethyl)-(2-chloro-3-trifluoromethylbenzyl)amine (73 mg, 0.19mmol), and potassium carbonate (26 mg, 0.21 mmol) in acetonitrile (5 ml)was stirred and heated to 50° C. for 5 hr. The reaction was cooled,diluted with water, and extracted with diethyl ether. The organicextracts were washed with water, dried, and the solvent removed. Theresidue was chromatographed over silica gel (hexane/methylenechloride/Diethyl ether:60/40/5) to give the title compound as an oil (35mg, 31%). MS (ESI) 594.2 (M+H)⁺.

f)(3-{4-[(2-Chloro-3-(trifluoromethyl)benzyl)-(2,2-diphenylethyl)-amino]butyl}phenyl)-aceticacid

A solution of(3-{4-[(2-chloro-3-(trifluoromethyl)benzyl)-(2,2-diphenylethyl)-amino]butyl}phenyl)-aceticacid methyl ester (29 mg, 0.05 mmol) and NaOH (126 mg, 3.15 mmol) inMeOH (3 ml) and water (1 ml) was heated to 50° for 30 minutes. Thereaction was cooled, neutralized with aqueous HCl (3.15 mmol), dilutedwith water and extracted with ethyl acetate. The extracts were dried andthe solvent evaporated. Trituration of the residue with cyclohexane gavethe title compound as a white powder (19 mg, 65%). MS (ESI) 580.2(M+H)⁺.

EXAMPLE 22 Preparation of(3-{3-[(4-Fluoro-3-methyl-benzyl)-((R)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-aceticacid

a) {3-[3-((R)-2-Phenyl-propylamino)-propoxy]-phenyl}-acetic acid methylester

[3-(3-Bromo-propoxy)-phenyl]-acetic acid methyl ester (11.48 g, 0.04mole) in acetonitrile (300 mL) was added dropwise over 45 minutes to amixture of (R)-2-Phenyl-propylamine (1.3 eq., 7.04 g, 0.052 mole),sodium iodide (18.0 g, 0.12 mole), and potassium carbonate (16.6 g, 0.12mole) in acetonitrile (2000 mL). The mixture was stirred five days. Thereaction mixture was filtered and the filter cake washed withacetonitrile (500 mL). The acetonitrile was evaporated and the residuedissolved in methylene chloride and washed with water(2×), dried overmagnesium sulfate, filtered and evaporated. The resulting residue waspurified by silica gel chromatography (using 3% to 10%methanol/methylene chloride as elutant) to give the title compound(10.19 g, 75%). MS (ESI) 342 (M+H)⁺.

b)(3-{3-[(4-Fluoro-3-methyl-benzyl)-((R)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-aceticacid

To a solution of{3-[3-((R)-2-Phenyl-propylamino)-propoxy]-phenyl}-acetic acid methylester (100 mg, 293 mmol) in methanol (1 ml) was added acetic acid (10%by volume) followed by 4-Fluoro-3-methyl-benzaldehyde (121 mg, 879 mmol)and sodium cyanoborohydride (54.5 mg, 879 mmol). After the resultingmixture was stirred for 18 h at RT water was added to quench thereaction. The solution was made basic by the addition of sodiumhydroxide and heated for 30 min. The sample concentrated in vacuo andpurified by preparative HPLC (YMC CombiPrep ODS-A, 50×20 mm, 20 mL/min,A: 0.1% trifluoroacetic acid in acetonitrile B: 0.1% aqueoustrifluoroacetic acid, A: 10 to 90% during 10 min, UV detection at 254nm) to give the title compound as a solid (71.6 mg, 54%). MS (ESI) 450.0(M+H)⁺.

EXAMPLE 23(3-{3-[Benzo[1,3]dioxol-5-ylmethyl-((R)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-aceticacid

Following the procedure of Example 22 exceptBenzo[1,3]dioxole-5-carbaldehyde was used instead of4-Fluoro-3-methyl-benzaldehyde, the title compound was isolated to givea white solid (49%). MS (ESI) 462.0 (M+H⁺).

EXAMPLE 24(3-{3-[(4-tert-Butyl-benzyl)-((R)-2-phenyl-propyl)-amino]-propoxy)-phenyl)-aceticacid

Following the procedure of Example 22 except 4-tert-Butyl-benzaldehydewas used instead of 4-Fluoro-3-methyl-benzaldehyde, the title compoundwas isolated to give a white solid (31%). MS (ESI) 474.0 (M+H⁺).

EXAMPLE 25(3-{3-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-((R)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-aceticacid

Following the procedure of Example 22 except2,3-Dihydro-benzo[1,4]dioxine-6-carbaldehyde was used instead of4-Fluoro-3-methyl-benzaldehyde, the title compound was isolated to givea white solid (97%). MS (ESI) 476.0 (M+H⁺).

EXAMPLE 26(3-{3-[(4-Methylsulfanyl-benzyl)-((R)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-aceticacid

Following the procedure of Example 22, 4-Methylsulfanyl-benzaldehyde wasused instead of 4-Fluoro-3-methyl-benzaldehyde, the title compound wasisolated to give a white solid (79%). MS (ESI) 464.0 (M+H⁺).

EXAMPLE 27(3-{3-[((R)-2-Phenyl-propyl)-(2,4,5-trifluoro-benzyl)-amino]-propoxy}-phenyl)-aceticacid

Following the procedure of Example 22, 2,4,5-Trifluoro-benzaldehyde wasused instead of 4-Fluoro-3-methyl-benzaldehyde, the title compound wasisolated to give a white solid (8.1%). MS (ESI) 472.0 (M+H⁺).

EXAMPLE 28(3-{3-[((R)-2-Phenyl-propyl)-(5-piperidin-1-yl-furan-2-ylmethyl)-amino]-propoxy}-phenyl)-aceticacid

Following the procedure of Example 22,5-Piperidin-1-yl-furan-2-carbaldehyde was used instead of4-Fluoro-3-methyl-benzaldehyde, the title compound was isolated to givea white solid (9.9%). MS (ESI) 491.0 (M+H⁺).

EXAMPLE 29(3-{3-[(4-Isopropyl-benzyl)-((R)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-aceticacid

Following the procedure of Example 22, 4-Isopropyl-benzaldehyde usedinstead of 4-Fluoro-3-methyl-benzaldehyde, the title compound wasisolated to give a white solid (16.6%). MS (ESI) 460.0 (M+H⁺).

EXAMPLE 302-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-propane-1,3-diolhydrochloride salt

a)(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-aceticacid methyl ester

To a solution of(3-{3[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-aceticacid hydrochloride salt (Example 1d, 0.1 g, 0.2 mmol) in methanol (2 ml)was added concentrated sulfuric acid (2 drops). After the resultingmixture was heated to reflux for 2 h solvent was removed under vacuum.The residue was dissolved in water and neutralized to pH=7. The aqueouslayer was extracted with ethyl acetate three times. The combined organiclayers were washed with, brine, dried over magnesium sulfate, andconcentrated in vacco to give 900 mg (93%) of the title compound as anoil. MS m/e 596.2 (M+H)⁺.

b)2-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-malonicacid monomethyl ester

To a solution of(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-aceticacid methyl ester (97 mg, 0.2 mmol) in dry THF (50 ml) was added lithiumdiisopropyl amide (400 uL, 1.0 mmol) dropwise at 0° C. After 20 min at0° C., CO₂ gas was bubbled through the mixture as it was warmed to roomtemperature. The reaction mixture was neutralized with 1N HCl and theresidue partitioned between water and ethyl acetate. The combinedorganic layers were washed with brine, dried over magnesium sulfate andconcentrated under vacuum. The crude product was purified by HPLC (YMCCombiPrep ODS-A, 50×20 mm, 20 mumin, A: acetonitrile B: water, A: 60 to100% during 10 min, UV detection at 254 nm) to give the title compoundas an oil (22 mg, 21%). MS m/e 640.2(M+H)⁺.

c)2-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-propane-1,3-diolhydrochloride salt

To2-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-malonicacid monomethyl ester (22 mg, 0.03 mmol) in diethyl ether (1 ml) wasadded lithium aluminum hydride (100 uL) at 0° C. The reaction wasallowed to warm to room temperature before the addition of brine andethyl acetate. The combined organic layers were dried over magnesiumsulfate and evaporated. The crude product was purified by HPLC (YMCCombiPrep ODS-A, 50×20 mm, 20 mL/min, A: acetonitrile B: water, A: 60 to100% during 10 min, UV detection at 254 nm) to give the title compoundfree amine as an oil. MS m/e 598.2(M+H)⁺. To a solution of the freeamine in diethyl ether was added HCl in diethyl ether (1.0M). Thesuspension was evaporated and dried to give the title compound as awhite solid (2 mg, 10%).

EXAMPLE 31N-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-carbamicacid tert-butyl ester

a) N-(3-Hydroxy-phenyl)-carbamic acid tert-butyl ester

3-aminophenol (2.0 g, 18.3 mmol) was dissolved in dioxane (50 mL) andwater (25 mL) and treated with triethylamine (3.8 mL, 27.5 mmol) anddi-tert-butyl-dicarbonate (6.0 g, 27.5 mmol) at room temperature. Thesolution was maintained for 18 hours and then the solvent was removedunder reduced pressure. The residue was purified by silica gelchromatography (35 g Redisep column, silica, 40 um, 60 Å, 35 mL/min, A:hexanes, B: EtOAc, B: 0% for 5 min, B: 0% to 50% over 30 min; detectionat 214 nm) to give 2.7 g (12.9 mmol, 71%) of the title compound as awhite solid. ¹H NMR (CDCl₃, 400 MHz) □: 7.2 (m, 2H), 6.8 (m, 1H), 6.5(m, 2H), 5.8 (bs, 1H), 1.5 (s, 9H);

b)N-(2,2-Diphenylethyl)-N-(3-hydroxy-propyl)-N-(2-chloro-3-trifluoromethyl-benzyl)amine

To a stirring solution of 3-bromo-propanol (5.9 mL, 65.4 mmol) inacetonitrile (500 ml) was added Nal (19.6 g, 131 mmol) and K₂CO₃ (18.1g, 131 mmol). The mixture was stirred at 85° C. for 1 h, and thenN-(2,2-diphenylethyl)-N-(2-chloro-3-trifluoromethyl-benzyl)amine (34.0g, 87.2 mmol) was added. The reaction mixture was heated at 85° C.overnight. Solvent was removed, the residue was washed with H₂O, andextracted twice with EtOAc. The EtOAc extracts were dried over Na₂SO₄,filtered, and concentrated. The crude mixture was purified by silica gelchromatography (35 g Redisep column, silica, 40 um, 60 Å, 35 mL/min, A:hexanes, B: EtOAc, B: 0% for 2 min, B: 0% to 10% over 10 min; B: 10% for2 min; B: 10% to 20% over 15 min; B: 20% for 2 min; B: 20% to 30% over40 min; detection at 214 nm) to give 13.3 g (29.7 mmol, 34%) of thetitle compound as a white solid. ¹H NMR (CDCl₃, 400 MHz) □: 7.6 (d,J=7.6 Hz, 1H), 7.3-7.1 (m, 12H), 4.2 (t, J=7.6 Hz, 1H), 3.8 (s, 2H), 3.6(t, J=5.6 Hz, 2H), 3.2 (d, J=7.6 Hz, 2H), 2.8 (t, J=6.0 Hz, 2H), 2.5 (s,1H), 1.7 (m, 2H);

c)N-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-carbamicacid tert-butyl ester

To a stirring solution of N-(3-Hydroxy-phenyl)-carbamic acid tert-butylester (1.9 g, 9.0 mmol) in anhydrous toluene (60 mL) was addedN-(2,2-diphenylethyl)-N-(3-hydroxy-propyl)-N-(2-chloro-3-trifluoromethyl-benzyl)amine(2.36 g, 5.3 mmol). Polymer bound triphenylphosphine (2.8 g, 8.4 mmol, 3mmol/g, Fluka Chemie) was then added, and the mixture stirred for 15minutes. The reaction mixture was then cooled to 0° C. anddiisopropylazodicarboxylate (1.28 mL, 6.5 mmol) was added in a dropwisefashion. After stirring at room temperature for 60 hours, the crudereaction mixture was filtered and the resulting solid was washed withtoluene. The filtrate was concentrated and the crude product waspurified by silica gel chromatography (35 g Redisep column, silica, 40um, 60 Å, 35 mL/min, A: hexanes, B: EtOAc, B: 0% for 5 min, B: 0% to 10%over 10 min; B: 10% for 10 min; B: 10% to 30% over 30 min; detection at214 nm) to give 2.0 g (3.1 mmol, 59% yield) of the title compound as awhite foam. MS (ESI) 639.4

EXAMPLE 323-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethylamino]-propoxy}-phenylamine

ToN-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-carbamicacid tert-butyl ester (492 mg, 0.77 mmol) dissolved in dioxane (5 mL)was added a 4.0 M solution of HCl in dioxane (5 mL). The solution wasmaintained for 20 hours after which the solvent was removed underreduced pressure. The residue was dissolved in dichloromethane andwashed twice with saturated NaHCO₃, dried over Na₂SO₄, and concentratedto give 0.4 g (0.74 mmol, 96%) of the title compound as a yellow oil. MS(ESI) 539.2

EXAMPLE 33N-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-acetamidehydrochloride salt

To3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethylamino]-propoxy}-phenylamine(80.0 mg, 0.15 mmol) dissolved in anhydrous dichloromethane (1 mL) wasadded pyridine (18 uL, 0.22 mmol) and acetyl chloride (12.7 uL, 0.18mmol) at room temperature. The reaction was maintained for 60 hoursafter which the solvent was removed under reduced pressure. The residuewas purified by preparative HPLC (YMC CombiPrep ODS-A, 50×20 mm, 20mL/min, A: acetonitrile B: water, A: 5 to 95% over 15 min, UV detectionat 214 nm and 254 nm) and the resulting residue after solvent removalwas treated with aqueous 6N HCl (0.5 mL) and acetonitrile (2 mL). Thesolvent was removed under reduced pressure to give 41.4 mg (0.07 mmol,47%) of the title compound as a colorless oil. MS (ESI) 581.0

EXAMPLE 34 Furan-2-carboxylic acidN-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-amidehydrochloride salt

Following the procedure of Example 33 except furan-2-carbonyl chloridewas used instead of acetyl chloride, the title compound was isolated togive 61.0 mg (0.096 mmol, 64%) of a colorless oil. MS (ESI) 633.0

EXAMPLE 35N-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-methanesulfonamidehydrochloride salt

Following the procedure of Example 33 except methanesulfonyl chloridewas used instead of acetyl chloride, the title compound was isolated togive 60.2 mg (0.098 mmol, 66%) of a colorless oil. MS (ESI) 617.2

EXAMPLE 36N-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}phenyl)-benzenesulfonamidehydrochloride salt

Following the procedure of Example 33 except benzenesulfonyl chloridewas used instead of acetyl chloride, the title compound was isolated togive 57.9 mg (0.085 mmol, 58%) of a colorless oil. MS (ESI) 679.0

EXAMPLE 371-(2-Chloro-phenyl)-3-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-ureahydrochloride salt

Following the procedure of Example 33 except 2-chlorophenyl isocyanatewas used instead of acetyl chloride, the title compound was isolated togive 41.0 mg (0.059 mmol, 40%) of a colorless oil. MS (ESI) 692.4

EXAMPLE 38N-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-N-methyl-amine

a)N-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-N-methyl-carbamicacid tert-butyl ester

N-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-carbamicacid tert-butyl ester (1.05 g, 1.64 mmol) was dissolved in anhydrous DMF(10 mL) and cooled to 0° C. under argon. NaH (78.8 mg, 1.97 mmol, 60%dispersion in mineral oil) was added and the mixture stirred at 0° C.for 30 minutes. Methyl iodide (164 uL, 2.63 mmol) was added and thereaction was allowed to warm to room temperature at which point thesolution was maintained for 18 hours. The reaction mixture was thenpoured into H₂O and extracted twice with EtOAc. The combined EtOAcextracts were washed with saturated aqueous NaCl, dried over Na₂SO₄,filtered, and concentrated to a yellow oil which was further purified bysilica gel chromatography (10 g Redisep column, silica, 40 um, 60 Å, 35mL/min, A: hexanes, B: EtOAc, B: 0% for 5 min, B: 0% to 10% over 10 min;B: 10% for 10 min; B: 10% to 30% over 15 min; B: 30% for 10 min;detection at 214 nm) to give 1.05 g (1.63 mmol, 99%) of the titlecompound as a yellow oil. MS (ESI) 653.2

b)N-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}phenyl)-N-methyl-amine

Following the procedure of Example 32 except thatN-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}phenyl)-N-methyl-carbamicacid tert-butyl ester was used instead ofN-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-carbamicacid tert-butyl ester, the title compound was isolated to give 422 mg(0.76 mmol, 48%) of a colorless oil. MS (ESI) 553.0

EXAMPLE 39N-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy)-phenyl)-N-methyl-acetamidehydrochloride salt

N-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-N-methyl-amino(54.0 mg, 0.098 mmol) was dissolved in anhydrous dichloromethane (1 mL)and treated with pyridine (12 uL, 0.15 mmol) and acetyl chloride (8.3uL, 0.12 mmol) at room temperature. The reaction was maintained for 60hours after which the solvent was removed under reduced pressure. Theresidue was purified by preparative HPLC (YMC CombiPrep ODS-A, 50×20 mm,20 mL/min, A: acetonitrile B: water, A: 5 to 95% over 15 min, UVdetection at 214 nm and 254 nm) and the resulting residue after solventremoval was treated with aqueous 6N HCl (0.5 mL) and acetonitrile (2mL). The solvent was removed under reduced pressure to give 30.3 mg(0.05 mmol, 52%) of the title compound as a colorless oil. MS (ESI)595.2

EXAMPLE 40 Furan-2-carboxylic acidN-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-N-methyl-amidehydrochloride salt

Following the procedure of Example 39 except furan-2-carbonyl chloridewas used instead of acetyl chloride, the title compound was isolated togive 54.1 mg (0.084 mmol, 86%) of a colorless oil. MS (ESI) 647.2

EXAMPLE 41N-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-N-methyl-methanesulfonamidehydrochloride salt

Following the procedure of Example 39 except methanesulfonyl chloridewas used instead of acetyl chloride, the title compound was isolated togive 47.9 mg (0.076 mmol, 78%) of a colorless oil. MS (ESI) 631.2

EXAMPLE 42N-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-N-methyl-benzenesulfonamidehydrochloride salt

Following the procedure of Example 39 except benzenesulfonyl chloridewas used instead of acetyl chloride, the title compound was isolated togive 48.5 mg (0.070 mmol, 72%) of a colorless oil. MS (ESI) 693.0

EXAMPLE 433-(2-Chloro-phenyl)-1-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-1-methyl-ureahydrochloride salt

Following the procedure of Example 39 except 2-chlorophenyl isocyanatewas used instead of acetyl chloride, the title compound was isolated togive 51.1 mg (0.072 mmol, 74%) of a colorless oil. MS (ESI) 706.0

EXAMPLE 44 Benzo[1,3]dioxole-5-carboxylic acidN-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-N-methyl-amidehydrochloride salt

Following the procedure of Example 39 except piperonyloyl chloride wasused instead of acetyl chloride, the title compound was isolated to give58.3 mg (0.083 mmol, 85%) of a colorless oil. MS (ESI) 701.2

EXAMPLE 451-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-3-(3,5-dimethoxy-phenyl)-1-methyl-ureahydrochloride salt

Following the procedure of Example 39 except 3,5-dimethoxyphenylisocyanate was used instead of acetyl chloride, the title compound wasisolated to give 55.8 mg (0.076 mmol, 78%) of a colorless oil. MS (ESI)732.2

EXAMPLE 46 Propane-1-sulfonic acid(5-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-2-methyl-phenyl)-amide

a) Propane-1-sulfonic acid (5-methoxy-2-methyl-phenyl)-amide

To the solution of 5-methoxy-2-methyl-phenylamine (0.118 g, 0.86 mmol)and pyridine (0.1 mL) and CH₂Cl₂ (3 mL) at 0° C. was added dropwisepropane-1-sulfonyl choride (0.135 g, 0.95 mmol) and the reaction mixturewas stirred at RT overnight. The mixture was then concentrated andpurified via silica gel chromatography to give the product as an oil(0.145 g, 69%): MS(ES) m/e 244.2 [M+H]⁺.

b) Propane-1-sulfonic acid (5-hydroxy-2-methyl-phenyl)-amide

To the solution of propane-1-sulfonic acid(5-methoxy-2-methyl-phenyl)-amide. (97 mg, 0.38 mmol) and CH₂Cl₂ (3 mL)at 0° C. was added dropwise boron tribromide (0.75 mL, 1M in CH₂Cl₂).The reaction mixture was stirred at 0° C. for 1 h then at RT for 1.5 h.The mixture was washed with H₂O and sat. NaHCO₃, extracted with CH₂Cl₂,dried over Na₂SO₄ and concentrated to give the product as a clear oil(47.1 mg, 54%): MS(ES) m/e 230.0 [M+H]⁺.

c) Propane-1-sulfonic acid(5-{3-[(chloro-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-2-methyl-phenyl)-amide

Following the procedure of Example 31c except propane-1-sulfonic acid(5-hydroxy-2-methyl-phenyl)-amide was used instead ofN-(3-Hydroxy-phenyl)-carbamic acid tert-butyl ester, the title compoundwas obtained as a clear oil (34.3 mg, 27%): MS(ES) m/e 659.4 [M+H]⁺.

EXAMPLE 473-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-2-methyl-phenylamine

a)(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(2-methyl-3-nitro-phenoxy)-propyl]-amine

Following the procedure of Example 1, step (a-b), except2-Methyl-3-nitrophenol was used instead of 3-hydroxyphenylacetate instep 1 (a) the title compound was prepared as an oil (2%). MS (ESI)583.4 (M⁺).

b)3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-2-methyl-phenylamine

(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(2-methyl-3-nitro-phenoxy)-propyl]-amine(300 mg, 0.51 mmol) was dissolved in methanol (100 ml), and hydrogenatedwith 10% Pd/C (40 mg) at 60 psi at room temperature. After 2.5 h, thereaction mixture was filtered and concentrated in vacuo to give an amberoil, 0.25 g (89%). Flash silica gel chromatography (Supelco DiscoveryDSC-Si) (CHCl₃) afforded the title compound as a pure oil (75%). MS(ESI) 552.5 (M−H⁺).

EXAMPLE 482-Chloro-5-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenylamine

a)(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(4-chloro-3-nitro-phenoxy)-propyl]-amine

Following the procedure of Example 1, step (a-b), except4-Chloro-3-nitrophenol was used instead of 3-hydroxyphenylacetate instep 1(a) the title compound was prepared as an oil (5%). MS (ESI) 603.2(M⁺).

b)2-Chloro-5-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenylamine

(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(4-chloro-3-nitro-phenoxy)-propyl]-amine(400 mg, 0.66 mmol) was hydrogenated over 10% Pd/C (40 mg) at 60 psi atroom temperature in the presence of 1N HCl-Et₂O (10 ml). After 24 h, thereaction mixture was filtered and concentrated in vacuo to give a heavyoil. HPLC purification of the crude amine (Phenomonex Luna Combi HTS, 5micron C₁₈, 275 mm×30 mm, 10% CH₃CN— water gradient to 95% CH₃CN)afforded the title compound as an oil. Treatment of the free base with1N HCl-Et₂O (excess), followed by filtration and isolation of theresulting precipitate gave the title compound as a brown solid, 18.5 mg(4.3%). MS (ESI) 572.5 (M⁺).

EXAMPLE 493-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-cyclopentyl-amine,dihydrochloride salt

a)(3-(3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenylaminedihydrochloride

(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-carbamicacid tert-butyl ester, (0.51 g, 0.8 mmol) was stirred overnight at roomtemperature in a mixture methylene chloride (5 mL) and trifluoroaceticacid (0.5 mL). The solvents were removed in vacuo to yield the crudeamine as an oil. The oil was diluted with ether, and 1 N HCl in Et₂O wasadded to precipitate the HCl salt of the product. The title compound wasisolated as a cream yellow powder, 0.53 g (100%). MS (ESI) 539 (M+H⁺).

b)(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-cyclopentyl-aminedihydrochloride salt

(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenylaminedihydrochloride (53 mg, 0.086 mmol) was diluted with absolute ethanol (3mL). Next, both cyclopentanone (7.2 mg, 0.086 mmol) and sodiumcyanoborohydride (19.2 mg, 0.3 mmol) were added to the solution. Thereaction mixture was stirred at room temperature overnight andconcentrated under a stream of argon. Water was added and the reactionmixture was extracted with ethyl acetate. The crude amine was purifiedby preparative HPLC chromatography (Varian Mega BondElut Si) to affordthe title compound as the free base. Addition of 1 N HCl in Et₂O gavethe title compound as a white powder, 22 mg (42%). MS (ESI) 608 (M+H⁺).

EXAMPLE 50(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-isopropyl-amine,dihydrochloride salt

Following the procedure of Example 49, steps (a-b), except acetone wasused in step 3(b) instead of cyclopentanone, the title compound wasisolated as a white solid, 16 mg (41%). MS (ESI) 582 (M+H⁺).

EXAMPLE 51Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}phenyl)-ethyl-amine,dihydrochloride salt

Following the procedure of Example 49, steps (a-b), except acetaldehydewas used in step 3(b) instead of cyclopentanone, the title compound wasisolated as a white solid, 10 mg (27%). MS (ESI) 567 (M+H⁺).

EXAMPLE 52(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-(3-methyl-butyl)-aminedihydrochloride salt

Following the procedure of Example 49, steps (a-b), except2-methylbutyraldehyde was used in step 3(b) instead of cyclopentanone,the title compound was isolated as a white solid, 7.0 mg (18%). MS (ESI)609 (M+H⁺).

EXAMPLE 53(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-isobutyl-aminedihydrochloride salt

Following the procedure of Example 49, steps (a-b), except2-isobutyraldehyde was used in step 3(b) instead of cyclopentanone, thetitle compound was isolated as a white solid, 5 mg (13%). MS (ESI) 595(M+H⁺).

EXAMPLE 54(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-(2,2,2-trifluoroethyl)-amine,dihydrochloride salt

Following the procedure of Example 49, steps (a-b), except2,2,2-trifluoroacetaldehyde was used in step 3(b) instead ofcyclopentanone, the title compound was isolated as a amber oil, 1.7 mg(3.5%). MS (ESI) 621 (M⁺).

EXAMPLE 55(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-cyclopropylmethy-l-aminedihydrochloride salt

Following the procedure of Example 49, steps (a-b), exceptcyclopropylcarboxaldehyde was used in step 3(b) instead ofcyclopentanone, the title compound was isolated as a white solid, 7.3 mg(19%). MS (ESI) 593 (M+H⁺).

EXAMPLE 56(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-(2-ethyl-butyl)-amine,dihydrochloride salt

Following the procedure of Example 49, steps (a-b), except2-ethylbutyraldehyde was used in step 3(b) instead of cyclopentanone,the title compound was isolated as a white solid, 7 mg (17%). MS (ESI)623 (M+H⁺).

EXAMPLE 57(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-(2,2-dimethyl-propyl)-amine,dihydrochloride salt

Following the procedure of Example 49, steps (a-b), exceptisovaleraldehyde was used in step 3(b) instead of cyclopentanone, thetitle compound was isolated as a white solid, 2.5 mg (6%). MS (ESI) 609(M+H⁺).

EXAMPLE 58(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-hexyl-aminedihydrochloride salt

Following the procedure of Example 49, steps (a-b), except valeraldehydewas used in step 3(b) instead of cyclopentanone, the title compound wasisolated as a white solid, 4.2 mg (10%). MS (ESI) 623 (M+H⁺).

EXAMPLE 59Butyl-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-aminedihydrochloride salt

Following the procedure of Example 49, steps (a-b), except butyraldehydewas used in step 3(b) instead of cyclopentanone, the title compound wasisolated as a white solid, 7.5 mg (20%). MS (ESI) 595 (M+H⁺).

EXAMPLE 60[1-(3-{3-[(2-Chloro-3-(trifluoromethyl)-benzyl)-(2,2-diphenylethyl)-amino]-propoxy}-phenyl-piperidine-4-carboxylicacid dihydrochloride

a) 1-(3-Oxo-cyclohex-1-enyl)-piperidine-4-carboxylic acid ethyl ester

The title compound was prepared according to the literature procedure:Lennon, M and Proctor, G. R. J. Chem. Soc, Perkins Trans. 1; 2009-2011,1979.

b) 1-(3-Hydroxy-phenyl)-piperidine-4-carboxylic acid ethyl ester

The title compound was prepared according to the literature procedureabove.

c)[1-(3-{3-[(2-Chloro-3-(trifluoromethyl)-benzyl)-(2,2-diphenylethyl)-amino]-propoxy}-phenyl-piperidine-4-carboxylicacid ethyl ester

To a stirring solution of 1-(3-hydroxyphenyl)-piperidine-4-carboxylicacid ethyl ester (0.19 g, 0.77 mmol) in 10 mL of anhydrous toluene wasadded3-[(2-chloro-3-(trifluoromethyl)-benzyl)-(2,2-diphenyl-ethyl)-amino]-propan-1-ol(0.41 g, 0.92 mmol). Polymer bound triphenyphosphine (0.41 g, 1,23 mmol,3 mmol/g, Fluka Chemie) was then added, and the mixture was reacted for15 minutes. The reaction mixture was then cooled to 0° C. anddiisopropylazodicarboxylate (0.2 g, 0.96 mmol) was added in a dropwisefashion. After stirring at RT overnight, the crude reaction mixture wasfiltered and the solid was washed with EtOAc. After concentration of thefiltrate in vacuo, the crude product was purified by columnchromatography over silica gel (silica gel 60, EM Science) using 10%EtOAc: hexane as eluent to afford 0.32 g (62%) of the title compound asan oil: MS(ESI) 679.0 (M+H⁺).

d)[1-(3-{3-[(2-Chloro-3-(trifluoromethyl)-benzyl)-(2,2-diphenylethyl)-amino]-propoxy}-phenyl-piperidine-4-carboxylicacid

To a stirring solution of[1-3-{[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy)-phenyl-piperidine-4-carboxylicacid ethyl ester (0.32 g, 0.47 mmol) in 7.0 mL of tetrahydrofuran and 3mL of water was added LiOH (0.042 g, 1 mmol). The reaction mixture wasstirred overnight Tetrahydrofuran was removed in vacuo and the residuewas diluted with water (3 mL), adjusted to pH=4, with dilute HCl, andextracted with EtOAc. The organic layer was washed with water, brine,dried over MgSO₄, filtered, and concentrated in vacuo to give 0.28 g(93%) of an oil. It was dissolved in THF-ether and acidified with 1.0 MHCl/Et₂O. More ether was added and filtered to afford the titlecompound. MS(ESI) 651.0 (M+H⁺).

EXAMPLE 61[1-(3-{3-[(2-Chloro-3-(trifluoromethyl)-benzyl)-(2,2-diphenylethyl)-amino]-propoxy}-phenyl-piperidine-4-yl-aceticacid dihydrochloride (GSK-174013A)

a) Piperidin-4-yl-acetic acid hydrochloride

A mixture of 4-pyridylacetic acid hydrochloride (5 g, 28.8 mmol),glacial acetic acid (100 mL) and PtO₂ (0.5 g) was hydrogenated at 50 psiovernight. The solvent was decanted from the catalyst and concentratedin vacuo. Azetroped with toluene twice then washed with ether to give 5g (97%) of white solid. MS(ESI) 144.0 (M+H⁺).

b) Piperidin-4-yl-acetic acid methyl ester hydrochloride

To a stirring suspension of piperidin-4-yl-acetic acid hydrochloride inMeOH (15 mL) at −5° C. was added thionyl chloride (1.12 mL, 15.3 mmol)dropwise. The reaction mixture was allowed to reach to RT then heated to40° C. for 4 h. The reaction mixture was concentrated in vacuo and theresulting white solid was azeotroped with toluene twice. Washed withether and filtered to give 2.7 g (quantitative yield). MS(ESI) 158.2(M+H⁺).

c) [1-(3-Oxo-cyclohex-1-enyl)-piperidin-4-yl]-acetic acid methyl ester

To piperidin-4-yl-acetic acid methyl ester hydrochloride (1.55 g, 8mmol) was added conc. NH₄OH (1 mL). This mixture was stirred for 5 min.and concentrated in vacuo and azetroped with toluene several times. Thenfresh toluene (80 mL) and cyclohexane-1,3-dione were added. Refluxed for3 h with a Dean-Stark Trap. Cooled and concentrated in vacuo. The crudeyellow oil was used in the next step without further purification (2.0g, quantitative yield): MS(ESI) 252.5 (M+H⁺).

d) [1-(3-Hydroxy-phenyl)-piperidin-4-yl]-acetic acid methyl ester

The title compound was prepared according to the literature procedure(Lennon, M and Proctor, G. R. J. Chem. Soc, Perkins Trans. 1;2009-2011(1979).

The crude product was purified by column chromatography over silica gel(Silica gel 60, EM Science) using 25% EtOAc: hexanes as eluent to affordan oil (33% over two steps). MS(ESI) 250.2 (M+H⁺)

e)[1-(3-{3-[(2-Chloro-3-(trifluoromethyl)-benzyl)-(2,2-diphenylethyl)-amino]-propoxy}-phenyl-piperidine-4-yl-aceticacid methyl ester

Following the procedure of Example 60(c) above except[1-(3-hydroxy-phenyl)-piperidin-4-yl]-acetic acid methyl ester was usedin step 60(c). instead of 1-(3-hydroxyphenyl)-piperidin-4-carboxylicacid ethyl ester. The title compound was isolated as an oil (38%).MS(ESI)679.2(M+H⁺)

f)[1-(3-{[3-(2-Chloro-3-(trifluoromethyl)-benzyl)-(2,2-diphenylethyl)-amino]-propoxy}-phenyl-piperidin-4-yl-aceticacid dihydrochloride

Following the procedure of Example 60(d) above except[1-(3-{3-[(2-Chloro-3-(trifluoromethyl)-benzyl)-(2,2-diphenylethyl)-amino]-propoxy}-phenyl-piperidin-4-yl-aceticacid methyl ester was used in step 60(d) instead of[1-(3-{3-[(2-Chloro-3-(trifluoromethyl)-benzyl)-(2,2-diphenylethyl)-amino]-propoxy}-phenyl-piperidine-4-carboxylicacid methyl ester, the title compound was obtained as white solid (81%)MS(ESI) 665.4 (M+H⁺).

EXAMPLE 62[4-(3-{3-[(2-Chloro-3-(trifluoromethyl)-benzyl)-(2,2-diphenylethyl-amino]-propoxy}-phenyl)-piperidin-1-yl]-aceticacid dihydrochloride (GSK-130932A)

a) 1-Benzyl-4-(3-methoxy phenyl)-piperidin-4-ol

The title compound was prepared according to the literature procedure:Sugg, E. E. and Portoghese, P. S., J. Med. Chem. 29, 2028-2033, 1986.

b) 1-Benzyl-4-(3-methoxy phenyl)-1,2,5,6-tetrahydro-pyridine

The title compound was prepared according to the same literaturereference above.

c) 4-(3-Methoxy-phenyl)-piperidine

The title compound was prepared according to a literature procedure:Komoto, T., et.al, Chem. Pharmn. Bull. 48(12), 1978-1985, 2000.

d) [4-(3-Methoxy-phenyl)-piperidin-1-yl]-acetic acid methyl ester

A mixture of 4-(3-Methoxy-phenyl)-piperidine (0.8 g, 4.2 mmol),methylbromoacetate (1.28 g, 8.38 mmol), diisopropylethylamine (3.7 mL,21 mmol) and MeOH (40 mL) was refluxed for 3 h. The reaction mixture wasconcentrated in vacuo, and the residue was partitioned between water andEtOAc and extracted. The organic layer was washed with water, brine,dried and concentrated in vacuo to give the title compound as an oil(1.0 g, 91% yield). MS(ESI) 264.2 (M+H⁺)

e) [4-(3-Hydroxy-phenyl)-piperidin-1-yl]-acetic acid hydrobromide

A mixture of [4-(3-methoxy-phenyl)-piperidin-1-yl]-acetic acid methylester and HBr (48%, 2 mL) was refluxed for 1 h. The reaction mixture wasconcentrated in vacuo, azeotroped with toluene twice and washed withether to give white solid (1.2 g, quantitative yield). MS(ESI) 236.0(M+H⁺)

f) [4-(3-Hydroxy-phenyl)-piperidin-1-yl]-acetic acid methyl ester

Following the procedure of Example 61(b) above except[4-(3-hydroxy-phenyl)-piperidin-1-yl]-acetic acid hydrobromide was usedin step 61 (b) instead of piperidin-4-yl-acetic acid hydrochloride, thetitle compound was obtained as an off-white solid (0.95 g, 76%). MS(ESI)250.2 (M+H⁺)

g)[4-(3-{3-[(2-Chloro-3-(trifluoromethyl)-benzyl)-(2,2-diphenylethyl)-amino]-propoxy}-phenyl)-piperidin-1-yl]-aceticacid methyl ester

Following the procedure of Example 60(c) except[4-(3-hydroxy-phenyl)-piperidin-1-yl]-acetic acid methyl ester was usedin step 60(c) instead of 1-(3-hydroxy-phenyl-piperidin-4-carboxylic acidethyl ester. The title compound was isolated as an oil (60% yield).MS(ESI) 679.2 (M+H⁺)

h)4-(3-{3-[(2-Chloro-3-(trifluoromethyl)-benzyl)-(2,2-diphenylethyl)-amino]-propoxy}-phenyl)-piperidin-1-yl]-aceticacid dihydrochloride

Following the procedure of Example 60(d) except4-(3-{3-[(2-Chloro-3-(trifluoromethyl)-benzyl)-(2,2-diphenylethyl)-amino]-propoxy}-phenyl)-piperidin-1-yl]-aceticacid methyl ester was used in step 60(d) instead of[1-(3-{3-[(2-Chloro-3-(trifluoromethyl)-benzyl)-(2,2-diphenylethyl)-amino]-propoxy}-phenyl-piperidine-4-carboxylicacid ethyl ester the title compound was prepared as a white solid (50%).MS(ESI) 665.4 (M+H⁺).

EXAMPLE 63rac-±-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(trifluoro-phenyl-propyl)-amino]-propoxy}-phenyl)-aceticacid

a)rac-±-(2-chloro-3-trifluoromethyl-benzyl)-(trifluoro-phenyl-propyl)-amine

To a stirring solution of α,α,α-trifluoromethylphenylacetaldehyde (C.Aaron, D. Dull, J. L. Schmiegel, D. Jaeger, Y. Ohashi, and H. S. Mosher,J. Org. Chem. 1967, 32, 2797) (0.70 g, 3.72 mmol) in ethanol (20 mL) wasadded 2-chloro-3-(α,α,α-trifluoromethyl)benzylamine (R. W. Fuller, B. B.Molloy, W. A. Day, B. W. Roush and M. M. Marsh, J. Med. Chem. 1973, 16,101) (806 mg, 3.84 mmol). To the stirring solution was added a catalyticamount of p-toluenesulfonic acid and sodium cyanoborohydride (0.21 g,3.34 mmol). The reaction mixture was stirred at room temperature for 1.5h and then diluted with water. Next, 3N HCl (aqueous) was added to givea clear solution which was extracted with diethyl ether. The aqueouslayer was separated and made basic by the addition of 2.5N aqueous NaOH.The basic layer was then extracted with diethyl ether. The combinedether extracts were dried (MgSO₄), filtered, and concentrated in vacuoto give an oil which was purified by flash silica gel chromatography(230-400 mesh, E. Merck) to give the title compound as a light yellowoil, 155 mg (11%). MS (ESI) 382.2 (M+H⁺).

b)rac-±-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(trifluoro-phenyl-propyl)-amino]-propoxy}-phenyl)-aceticacid

Following the procedure of Example 1, steps (a)-(d), exceptrac-±-(2-Chloro-3-trifluoromethyl-benzyl)-(trifluoro-phenyl-propyl)-aminewas used in step 1 (c) instead of[2-chloro-3-(trifluoromethyl)benzyl]-2,2-diphenylethylamine the titlecompound was synthesized, 17.6 mg (2.5%), as an oil. MS (ESI) 574.5(M+H⁺).

EXAMPLE 64rac-±-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2-dimethylamino-2-phenyl-ethyl)-amino]-propoxy}-phenyl)-aceticacid

a)rac-±-N²-2-Chloro-3-trifluoromethyl-benzyl)-N¹N¹-dimethyl-1-phenyl-ethane-1,2-diamine

To a stirring solution of rac-±-(2-Amino-1-phenethyl)dimethyl amine (500mg, 3.04 mmol) in methylene chloride (15 mL) was added2-chloro-3-trifluoromethyl benzaldehyde (0.70 g, 3.35 mmol) and sodiumtriacetoxyborohydride (0.71 g, 3.35 mmol) and glacial acetic acid (0.5mL). The reaction mixture was stirred under an argon atmosphere at RTovernight The methylene chloride solvent was removed under a stream ofargon and the resulting heavy oil was diluted with ethyl acetate andwater. Saturated aqueous sodium bicarbonate was added. The ethyl acetatesolution was separated, dried (MgSO₄), filtered, and concentrated invacuo to afford an oil. Purification by flash silica gel chromatography(230-400 mesh, E. Merck) gave the title compound as an oil, 270 mg(25%). MS (ESI) 563.5 (MH⁺).

b)rac-±-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2-dimethylamino-2-phenyl-ethyl)-amino]-propoxy}-phenyl)-aceticacid

Following the procedure of Example 1, steps (a)-(d), exceptrac-±-N²-2-Chloro-3-trifluoromethyl-benzyl)-N¹N′-dimethyl-1-phenyl-ethane-1,2-diaminewas used in step 1(c) instead of[2-chloro-3-(trifluoromethyl)benzyl]-2,2-diphenylethylamine the titlecompound was synthesized as a white solid, 26 mg (5.5%). MS (ESI) 549.5(M+H⁺).

EXAMPLE 65rac-±-(3-{3-[(2-Chloro-3-Trifluoromethyl-benzyl)-(2-morpholin-4-yl-2-phenyl-ethyl)-amino]-propoxy}-phenyl)-aceticacid

a)rac-±-(2-Chloro-3-trifluoromethyl-benzyl)-(morpholin-4-yl-phenyl-ethyl)-amine

Following the procedure (preparation ofrac-±-(2-chloro-3-trifluoromethyl-benzyl)-(trifluoro-phenyl-propyl)-amine)of Example 64, step (a) except rac-±-2-Morpholin4-yl-2-phenyl-ethylaminewas used in step (a) instead of2-chloro-3-(α,α,α-trifluoromethyl)benzylamine, and2-chloro-3-trifluoromethyl benzaldehyde was used instead of(α,α,α-trifluoromethylphenylacetaldehyde, the title compound wassythesized as an oil, 0.27 g (88%); MS (ESI) 399 (M+H⁺).

b)rac-±-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2-morpholin-4-yl-2-phenyl-ethyl)-amino]-propoxy}-phenyl)-aceticacid

Following the procedure of Example 1, steps (a)-(d) exceptrac-±-(2-Chloro-3-trifluoromethyl-benzyl)-(morpholin-4-yl-phenyl-ethyl)-aminewas used in step 1(c) instead of[2-chloro-3-(trifluoromethyl)benzyl]-2,2-diphenylethylamine the titlecompound was synthesized as an oil, 15.2 mg (3%); MS (ESI) 591 (M+H⁺).

EXAMPLE 66(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(6-morpholin-4-yl-pyridin-2-yloxy)-propyl]-aminehydrochloride salt

a) 6-Morpholin-4-yl-pyridin-2-ol

To a stirring solution of morpholine (10 ml) was added6-chloro-2-pyridinol (1.5 g, 11.57 mmol) and the mixture was heated at90° C. for 60 h. The reaction mixture was cooled to RT and concentratedunder reduced pressure (while heating) to afford the title compound as abrown solid (85%. The crude material was used without furtherpurification. MS (ESI) 181.2 (M+H⁺).

b)(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(6-morpholin-4-yl-pyridin-2-yloxy)-propyl]-aminehydrochloride salt

Following the procedure of Example 6(d), except6-morpholin-4-yl-pyridin-2-ol andN-(2,2-Diphenylethyl)-N-(3-hydroxy-propyl)-N-(2-chloro-3-trifluoromethyl-benzyl)aminewere used instead of 5-(3-hydroxy-benzyl)-ethoxymethyl-1,2,3,4-tetrazoleand 3-bromo-propanol in step 6(d), the title compound was synthesized asthe free base. The tertiaryamine was then dissolved in diethyl ether andacidified with 1.0 M HC/diethyl ether to give 90 mg (32% yield) of thetitle compound as a white solid. MS (ESI) 610.2 (M⁺).

EXAMPLE 67[3-(6-Chloro-pyridin-2-yloxy)-propyl]-(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-aminehydrochloride salt

Following the procedure of Example 6(d), except 6-chloro-2-pyridinol(Aldrich) andN-(2,2-Diphenylethyl)-N-(3-hydroxy-propyl)-N-(2-chloro-3-trifluoromethyl-benzyl)aminewere used instead of 5-(3-hydroxy-benzyl)-ethoxymethyl-1,2,3,4-tetrazoleand 3-bromo-propanol in step 6(d), the title compound was synthesized asthe free base. The tertiaryamine was then dissolved in diethyl ether andacidified with 1.0 M HCl/diethyl ether to give 90 mg (32% yield) of thetitle compound as a white solid. MS (ESI) 559.0 (M⁺).

EXAMPLE 68(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[6-(4-methyl-piperazin-1-yl)-pyridin-2-yloxy]-propyl}-aminedimesylate salt

a) 6-(4-Methyl-piperazin-1-yl)-pyridin-2-ol

To a stirring solution of 1-methyl-piperazine (10 ml) was added6-chloro-2-pyridinol (1.5 g, 11.57 mmol) and the mixture was heated at90° C. for 60 h. The reaction mixture was cooled to RT and concentratedunder reduced pressure (while heating) to afford the title compound as abrown solid (66%). The crude material was used without furtherpurification. MS (ESI) 194.2 (M+H⁺).

b)(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[6-(4-methyl-piperazin-1-yl)-pyridin-2-yloxy]-propyl}-aminedimesylate salt

Following the procedure of Example 6(d), except6-(4-methyl-piperazin-1-yl)-pyridin-2-ol andN-(2,2-Diphenylethyl)-N-(3-hydroxy-propyl)-N-(2-chloro-3-trifluoromethyl-benzyl)aminewere used instead of 5-(3-hydroxy-benzyl)-ethoxymethyl-1,2,3,4-tetrazoleand 3-bromo-propanol in step 6(d), the title compound was synthesized asthe free base. The tertiaryamine was then dissolved in dichloromethaneand two equivalents of methanesulfonic acid were added to afford thetitle compound as the dimesylate salt, 47 mg (19% yield), as a whitesolid. MS (ESI) 623.4 (M⁺).

EXAMPLE 69(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(6-piperazin-1-yl-pyridin-2-yloxy)-propyl]-aminehydrochloride salt

a) 4-(6-Hydroxy-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butylester

To a stirring solution of 6-piperazin-1-yl-pyridin-2-ol (0.6 g, 3.30mmol—Pavia, M. R., Taylor, C. P., Hershenson, F. M., Lobbestael, S. J.J. Med. Chem. 1987, 30(7), 1210) in 1,4-dioxane (15 ml) was addedt-BOC₂O (0.80 g, 3.68 mmol) and H₂O (3 ml). The reaction mixture washeated at 75° C. for 8 h and cooled to RT. The heterogenous mixture wasfiltered and concentrated. Purification by flash silica gelchromatography afforded the title compound as a red solid, 0.90 g (97%).MS (ESI) 280.4 (M+H⁺).

b)[4-{6-(3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-pyridin-2-yl)-piperazine-1-carboxylicacid tert-butyl ester

Following the procedure of Example 6(d), except4-(6-Hydroxy-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl esterandN-(2,2-Diphenylethyl)-N-(3-hydroxy-propyl)-N-(2-chloro-3-trifluoromethyl-benzyl)aminewere used instead of 5-(3-hydroxy-benzyl)-ethoxymethyl-1,2,3,4-tetrazoleand 3-bromo-propanol in step 6(d), the title compound was synthesized asthe free base, 0.46 g (52% yield), as a white solid. MS (ESI) 709.4(M⁺).

c)(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(6-piperazin-1-yl-pyridin-2-yloxy)-propyl]-aminehydrochloride salt

To a stirring solution of[4-{6-(3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-pyridin-2-yl)-piperazine-1-carboxylicacid tert-butyl ester (40 mg, 0.05 mmol) in methanol (0.8 ml) was added1 N HCl in Et₂O. The reaction mixture was stirred at RT for 4 h andconcentrated under vacuum to provide the title compound as an off-whitesolid, 31 mg (91%). MS (ESI) 609.2 (M⁺).

EXAMPLE 70[4-(6-{3-[(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-pyridin-2-yl)-piperazin-1-yl]-aceticacid hydrochloride salt

a)[4-(6-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-pyridin-2-yl)-piperazin-1-yl]-aceticacid methyl ester

To a stirring solution of(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(6-piperazin-1-yl-pyridin-2-yloxy)-propyl]-aminehydrochloride (0.1 g, 0.16 mmol) in EtOH (6 ml) was added methylbromo-acetate (16 uL, 0.17 mmol) and diisopropylethylamine (89 uL, 0.51mmol). The reaction mixture was stirred for 10 h at RT and thenconcentrated. Purification by flash silica gel chromatograpy affordedthe title compound as a clear oil, 47 mg (42%). MS (ESI) 681.2 (M⁺).

b)[4-(6-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-pyridin-2-yl)-piperazin-1-yl]-aceticacid hydrochloride salt

To a stirring solution of[4-(6{-3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-pyridin-2-yl)-piperazin-1-yl]-aceticacid methyl ester (46 mg, 0.07 mmol) in THF (2 ml) and H₂O (0.5 ml) wasadded LiOH (6 mg, 0.13 mmol). The reaction mixture was stirred for 24 hat RT and then concentrated. The aqueous mixture was acidified to pH=3with 1 N HCl (aq) and extracted with EtOAc (three times). The organicextracts were dried over Na₂SO₄, filtered, and concentrated. The freebase was dissolved in dichloromethane and 1 N HCl (Et₂O) was added. Thesolution was concentrated under vacuum to provide the title compound asa white solid, 26 mg (45%). MS (ESI) 667.2 (M⁺).

EXAMPLE 712-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl]((S)-2-phenyl-propyl)amino]-(R)-1-methyl-propoxy}-phenyl)aceticacid hydrochloride salt

a)2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl]((S)-2-phenyl-propyl)amino]-(R)-1-methyl-propoxy}-phenyl)aceticacid methyl ester

Following the procedure of Example 4(a)-(c), except(S)-(2-Chloro-3-trifluoromethyl-benzyl)-(2-phenyl-propyl)-amine insteadof N-(2,2-diphenylethyl)-N-(2-chloro-3-trifluoromethyl)amine in step4(b) the title compound was obtained as a white powder (10% overall). MS(ESI) 548.0 (M⁺).

b)2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl]((S)-2-phenyl-propyl)amino]-(R)-1-methyl-propoxy}-phenyl)aceticacid hydrochloride salt

Following the procedure of Example 2, except2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl]((S)-2-phenyl-propyl)amino]-(R)-1-methyl-propoxy}-phenyl)aceticacid methyl ester was used instead of(R)-2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]-2-methyl-propoxy}-phenyl)aceticacid methyl ester, the title compound was isolated to give a whitesolid, 65 mg (95% yield). MS(ESI) 534.0(M⁺).

EXAMPLE 722-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl]((S)-2-phenyl-propyl)amino]-(R)-1-methyl-propoxy}-phenyl)ethanol

A solution of2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl]((S)-2-phenyl-propyl)amino]-(R)-1-methyl-propoxy}phenyl)aceticacid methyl ester (20 mg, 0.036 mmol) in THF (1 ml) at 0° C., wastreated with LiAlH₄ (100 uL of a 1N solution in THF), and the reactionwas stirred at 0° for 45 minutes. Ethyl acetate (1 ml) was added, thereaction warmed to RT, and water (2 ml) was added. The mixture wasextracted with ethyl acetate. The organic extracts were dried and thesolvent removed. The residue was chromatographed over silica gel(hexane/Ethyl acetate:3/7) to give the title compound as a pure oil (15mg, 91%). MS (ESI) 520.0 (M+H)⁺.

EXAMPLE 732-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl]((S)-2-phenyl-propyl)amino]-(R)-2-methyl-propoxy}-phenyl)aceticacid hydrochloride salt

a)2-(3-{3-[((S)-2-phenyl-propyl)amino](R)-2-methyl-propoxy}-phenyl)aceticacid methyl ester

To a stirring solution of (S)-[3-(2-methyl-3-bromopropoxy)phenyl]aceticacid methyl ester (450 mg, 1.49 mmol) and(S)-(−)-β-methylphenylethylamine (214 uL, 1.49 mmol) in acetonitrile (15mL) was added solid K₂CO₃ (620 mg, 4.5 mmol) and NaI (672 mg, 4.5 mmol).The reaction was heated to reflux and stirred overnight. Upon cooling toroom temperature, the reaction was filtered, washed with acetonitrile,and the filtrate was concentrated. The crude product was purified byflash silica gel chromatography (1:1 hexane to EtOAc) to give 268 mg(50% yield) of title compound as a viscous oil. MS(ESI) 356.0 (M+H⁺).

b)2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl]((S)-2-phenyl-propyl)amino]-(R)-2-methyl-propoxy}-phenyl)aceticacid methyl ester

Following the procedure of Example 7(d), except2-(3-{3-[((S)-2-phenyl-propyl)amino](R)-2-methyl-propoxy}-phenyl)aceticacid methyl ester was used instead of(R)-2-(3-{3-(2,2-diphenylethyl)amino]-3-methyl-propoxy}-phenyl)aceticacid methyl ester in step (d) the title compound was obtained as a whitepowder, 277 mg (67%). MS (ESI) 548.2 (M⁺).

c)2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl]((S)-2-phenyl-propyl)amino]-(R)-2-methyl-propoxy}-phenyl)aceticacid hydrochloride salt

Following the procedure of Example 2, except2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl]((S)-2-phenyl-propyl)amino]-(R)-2-methyl-propoxy}-phenyl)aceticacid methyl ester was used instead of(R)-2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]-2-methyl-propoxy}-phenyl)aceticacid methyl ester, the title compound was isolated to give a whitesolid, 95 mg (97% yield). MS(ESI) 534.2 (M⁺).

EXAMPLE 742-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl]((S)-2-phenyl-propyl)amino]-(R)-2-methyl-propoxy}-phenyl)ethanol

Following the procedure of Example 72 (above) except2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl]((S)-2-phenyl-propyl)amino]-(R)-2-methyl-propoxy}-phenyl)aceticacid methyl ester was used instead of2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl]((S)-2-phenyl-propyl)amino]-(R)-1-methyl-propoxy}-phenyl)aceticacid methyl ester, the title compound was isolated to give a whitesolid, 47 mg (99% yield). MS(ESI) 520.2 (M⁺).

EXAMPLE 752-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl]((R)-2-phenyl-propyl)amino]-(R)-2-methyl-propoxy}-phenyl)aceticacid hydrochloride salt

a)2-(3-{3-[((R)-2-phenyl-propyl)amino]-(R)-2-methyl-propoxy}phenyl)aceticacid methyl ester

Following the procedure of Example 73(a) (above) except(R)-(−)-β-methylphenylethylamine was used instead of and(S)-(−)-β-methylphenylethylamine in step (a) the title compound wasobtained as a white powder, 270 mg (51%). MS (ESI) 356.0 (M+H⁺).

b)2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl]((R)-2-phenyl-propyl)amino]-(R)-2-methyl-propoxy}-phenyl)aceticacid methyl ester

Following the procedure of Example 7(d), except2-(3-{3-[((R)-2-phenyl-propyl)amino] (R)-2-methyl-propoxy}-phenyl)aceticacid methyl ester was used instead of(R)-2-(3-{3-(2,2-diphenylethyl)amino]-3-methyl-propoxy}-phenyl)aceticacid methyl ester in step (d) the title compound was obtained as a whitepowder, 271 mg (66%). MS (ESI) 548.2 (M⁺).

c)2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl]((R)-2-phenyl-propyl)amino]-(R)-2-methyl-propoxy}-phenyl)aceticacid hydrochloride salt

Following the procedure of Example 2, except2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl]((R)-2-phenyl-propyl)amino]-(R)-2-methyl-propoxy}-phenyl)aceticacid methyl ester was used instead of(R)-2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]-2-methyl-propoxy}-phenyl)aceticacid methyl ester, the title compound was isolated to give a whitesolid, 140 mg (96% yield). MS(ESI) 534.2 (M⁺).

EXAMPLE 762-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl]((R)-2-phenyl-propyl)amino]-(R)-2-methyl-propoxy}-phenyl)ethanol

Following the procedure of Example 72 (above) except2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl]((R)-2-phenyl-propyl)amino]-(R)-2-methyl-propoxy}-phenyl)aceticacid methyl ester was used instead of2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl]((S)-2-phenyl-propyl)amino]-(R)-1-methyl-propoxy}-phenyl)aceticacid methyl ester, the title compound was isolated to give a whitesolid, 87 mg (92% yield). MS(ESI) 520.2 (M⁺).

EXAMPLE 77(R)-2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]-2-methyl-propoxy}-phenyl)ethanol

Following the procedure of Example 72 (above) except(R)-2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]-2-methyl-propoxy}-phenyl)aceticacid methyl ester was used instead of2-(3-{3-{[2-Chloro-3-(trifluoromethyl)benzyl]((S)-2-phenyl-propyl)amino]-(R)-1-methyl-propoxy}-phenyl)aceticacid methyl ester, the title compound was isolated to give a whitesolid, 78 mg (59% yield). MS(ESI) 582.4 (M⁺).

EXAMPLE 783-{3-[(3-Chloro-2-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy-N,N-dimethyl-benzenesulfonamidehydrochloride

a) 3-Methoxy-N,N,-dimethyl-benzenesulfonamide

Dimethylamine (40% in H₂O, 1 mL) was added to a solution of3-methoxybenzenesulfonyl chloride (0.50 g, 2.4 mmol) and pyridine (1 mL)in THF (5 mL). The reaction mixture was allowed to stir at rt for 48 h,then was poured into H₂O and extracted with EtOAc. The organic extractswere washed with brine, dried (MgSO₄), filtered and concentrated to givean oil which was chromatographed (10-80% EtOAc in hexane) to give 0.400g (76%) of the title compound. MS (ESI) 216 (M+H⁺).

b) 3-Hydroxy-N,N,-dimethyl-benzenesulfonamide

A solution of BBr₃ (1 M in CH₂Cl₂, 2.0 mL, 2.0 mmol) was added dropwiseto a −78° C. solution of 3-methoxy-N,N,-dimethyl-benzenesulfonamide(0.15 g, 0.7 mmol) in CH₂Cl₂ (2 mL). The mixture was warmed to rt andstirred for 2 h, then cooled to 0° C. and quenched with saturated NaCO₃.The aqueous phase was neutralized with saturated NH₄Cl and extractedwith EtOAc. The organic extracts were washed with brine, dried (MgSO₄),filtered and concentrated to give an oil which was directly in the nextstep. MS (ESI) 202 (M+H⁺).

c)3-{3-[(3-Chloro-2-trifluoromethyl-benzyl)-diphenylethyl-amino}-propoxy-N,N-dimethyl-benzenesulfonamidehydrochloride

DIAD (48 uL, 0.24 mmol) was added dropwise to a RT solution of3-hydroxy-N,N,-dimethyl-benzenesulfonamide (0.040 g, 0.2 mmol),3-[(3-chloro-2-trifluoromethyl-benzyl)-diphenylethyl-amino]-propan-1-ol(0.088 g, 0.2 mmol) and triphenylphosphine (0.063 g, 0.24 mmol). Themixture was stirred for 48 at rt than was concentrated and purified byreverse phase HPLC to provide a solid which was dissolved in CH2Cl2 andtreated with excess 4M HCl in diethyl ether. The mixture wasconcentrated to provide 35 mg (25%) of the title compound. MS (ESI) 632(M+H⁺).

EXAMPLE 79 Cyclopropanecarboxylic acid3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-benzylamide

a) (3-Hydroxy-benzyl)-carbamic acid tert butyl ester

3-hydroxybenzylamine (Apin, 1.0 g, 8.1 mmole) was dissolved in DMF(25ml). Triethylamine (0.33 ml, 2.4 mmole) and (BOC)₂O (1.8 g, 8.1 mmole)were added, the mixture stirred over night at room temperature underargon atmosphere. The reaction was concentrated, chromatographed onsilica gel (0 to 20% EtOAc/hexanes) to give the titled compound (400 mg,22%). MH⁺223.0

b)(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-benzyl)-carbamicacid tert-butyl ester

(3-Hydroxy-benzyl)-carbamic acid tert butyl ester was dissolved in THF,triphenylphosphine (0.44 g, 2.2 mmole),3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethylamino]-propoxy}-phenylamine(1.0 g, 2.3 mmole) and DIAD (0.43 ml, 2.2 mmole) were addedsubsequently. The mixture was stirred overnight at room temperature. Thereaction was concentrated, chromatographed on silica gel (0 to 15%EtOAc/hexanes) to give the titled compound (0.51 g, 48%). MH⁺652.0

c)[3-(3-Aminomethyl-phenoxy)-propyl]-(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-aminedihydrochloride

(3-{3-[(Chloro-trifuoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-benzyl)-carbamicacid tert-butyl ester (530 mg, 0.8 mmole) was treated with 1 M HCl inether (8 ml). The mixture stirred 2 hours at room temperature underargon atmosphere. Solid precipitated, ether was decanted and solidwashed with ether (10 ml) twice, then dried under vacuum. (430 mg, 86%)MH⁺552.0

d) Cyclopropanecarboxylic acid3-{3-[(chloro-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-benzylamide

([3-(3-Aminomethyl-phenoxy)-propyl]-(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amine)(40 mg, 0.06 mmole) was dissolved in CH2Cl2 (1 ml), triethylamine (25uL) and cyclopropane carbonyl chloride (12.0 mg, 0.12 mmole) were added.The mixture was stirred overnight at room temperature under argonatmosphere, concentrated to dryness in vacuo purified on reversed phasegradient HPLC (YMC CombiPrep ODS-A, 50×20 mm, 20 mL/min, A: 0.1%trifluoroacetic acid in acetonitrile B: 0.1% aqueous trifluoroaceticacid, A: 10 to 90% during 10 min, UV detection at 254 nm) to give aclear film (28 mg, 75%). MH⁺=621.2.

The following Examples, 80-83, were prepared following the procedure forExample 79 with an alternate acid chloride in step d.

Structural Final Compound Acid Chloride Data 80N-(3-{3-[(2-Chloro-3-tri-fluoromethyl-benzyl)-di-phenylethyl-amino]-propoxy}-benzyl)-isobutyramide

MS(ES+)623.2[M + H]⁺ 81 Acetic acid(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-di-phenylethyl-amino]-propoxy}-benzylcarbamoyl)-methylester

MS(ES+)653.4[M + H]⁺ 82 N--(3-{3-[(2-Chloro-3-tri-fluoromethyl-benzyl)-di-phenylethyl-amino]-propoxy}-benzyl)-propionamide

MS(ES+)609.0[M + H]⁺ 83 2,5-Dimethyl-2-H-pyrazole-3-carboxylic acid3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-benzylamide

MS(ES+)675.0[M + H]⁺

EXAMPLE 84(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-(3-o-tolyloxy-propyl)-amine

To a solution of3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propan-1-ol(0.065 g, 0.145 mmol) in toluene (4 ml) at ambient temperature was addedo-cresol (0.020 g, 0.186 mmol) under Argon with stirring. The mixturewas treated with polymer bound PPh₃ (0.076 g, 0.228 mmol). After 15minutes of stirring, the mixture was treated with DIAD (0.036 g, 0.178mmol) and was stirred at ambient temperature overnight. The reactionmixture was filtered then concentrated, in vacuo, to dryness. The oilwas dissolved in DMSO and was purified via reverse-phase HPLC to yieldthe title compound (0.033 g, 42%); MS (ES+) m/e 539 [M+H]⁺.

The following Examples, 85-107, were prepared following the procedurefor Example 84 with an alternate phenol.

Character- Example Phenol isation 85 2-{3-[(2-Chloro-3- 2-CyanophenolMS(ES+) trifluoromethyl-benzyl)- m/e 550 diphenylethyl-amino]- [M + H]⁺propoxy}-benzonitrile 86 3-{3-[(2-Chloro-3- 3-Cyanophenol MS(ES+)trifluoromethyl-benzyl)- m/e 550 diphenylethyl-amino]- [M + H]⁺propoxy}-benzonitrile 87 [3-(3-Chloro-phenoxy)- 3-Chlorophenol MS(ES+)propyl]-(2-chloro-3- m/e 559 trifluoromethyl-benzyl)-(2,2- [M + H]⁺diphenyl-ethyl)-amine 88 (2-Chloro-3-trifluoromethyl- 2-MethoxyphenolMS(ES+) benzyl)-(2,2-diphenyl- m/e 555 ethyl)-[3-(2-methoxy- [M + H]⁺phenoxy)-propyl]-amine 89 [3-(2-Chloro-phenoxy)- 2-Chlorophenol MS(ES+)propyl]-(2-chloro-3- m/e 559 trifluoromethyl-benzyl)-(2,2- [M + H]⁺diphenyl-ethyl)-amine 90 (2-Chloro-3-trifluoromethyl- Phenol MS(ES+)benzyl)-(2,2-diphenyl- m/e 525 ethyl)-(3-phenoxy-propyl)- [M + H]⁺ amine91 (2-Chloro-3-trifluoromethyl- 3-Isopropylphenol MS(ES+)benzyl)-(2,2-diphenyl- m/e 567 ethyl)-[3-(3-isopropyl- [M + H]⁺phenoxy)-propyl]-amine 92 (2-Chloro-3-trifluoromethyl- 4-MethoxyphenolMS(ES+) benzyl)-(2,2-diphenyl- m/e 555 ethyl)-[3-(4-methoxy- [M + H]⁺phenoxy)-propyl]-amine 93 3-{3-[(Chloro- 3-Hydroxyphenol MS(ES+)trifluoromethyl-benzyl)- m/e 541 diphenylethyl-amino]- [M + H]⁺propoxy}-phenol 94 2-{3-[(Chloro- 2-Hydroxyphenol MS(ES+)trifluoromethyl-benzyl)- m/e 541 diphenylethyl-amino]- [M + H]⁺propoxy}-phenol 95 3-{3-[(Chloro- 3-Aminophenol MS(ES+)trifluoromethyl-benzyl)- m/e 540 diphenylethyl-amino]- [M + H]⁺propoxy}-phenylamine 96 (2-Chloro-3-trifluoromethyl- 3- MS(ES+)benzyl)-(2,2-diphenyl- Trifluoromethylphenol m/e 593ethyl)-[3-(3-trifluoromethyl- [M + H]⁺ phenoxy)-propyl]-amine 971-(3-{3-[(Chloro- 3- MS(ES+) trifluoromethyl-benzyl)-Hydroxyacetophenone m/e 567 diphenylethyl-amino]- [M + H]⁺propoxy}-phenyl)-ethanone 98 (3-{3-[(2-Chloro-3- 3-Phenylamino- MS(ES+)trifluoromethyl-benzyl)- phenol m/e 616 diphenylethyl-amino]- [M + H]⁺propoxy}-phenyl)-phenyl- amine 99 [3-(Benzo[1,3]dioxol-5- sesamolMS(ES+) yloxy)-propyl]-(2-chloro-3- m/e 569trifluoromethyl-benzyl)-(2,2- [M + H]⁺ diphenyl-ethyl)-amine 100(2-Chloro-3-trifluoromethyl- m-Cresol MS(ES+) benzyl)-(2,2-diphenyl- m/e539 ethyl)-(3-m-tolyloxy-propyl)- [M + H]⁺ amine 101(2-Chloro-3-trifluoromethyl- 3-Methoxyphenol MS(ES+)benzyl)-(2,2-diphenyl- m/e 555 ethyl)-[3-(3-methoxy- [M + H]⁺phenoxy)-propyl]-amine 102 (2-Chloro-3-trifluoromethyl- 3-IsobutylphenolMS(ES+) benzyl)-(2,2-diphenyl- m/e 581 ethyl)-[3-(3-isobutyl- [M + H]⁺phenoxy)-propyl]-amine 103 [3-(3-Butyl-phenoxy)- 3-Butylphenol MS(ES+)propyl]-(2-chloro-3- m/e 581 trifluoromethyl-benzyl)-(2,2- [M + H]⁺diphenyl-ethyl)-amine 104 (2-Chloro-3-trifluoromethyl- 3-(2,2-Dimethyl-MS(ES+) benzyl)-{3-[3-(2,2-dimethyl- propyl)-phenol m/e 595propyl)-phenoxy]-propyl}- [M + H]⁺ (2,2-diphenyl-ethyl)-amine

EXAMPLE 105(4-{3-[(2-Chloro-3-trifuoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-benzyl)-methyl-amine

a)4-{3-[(Chloro-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-benzaldehyde

To a solution of3-[(Chloro-trifluoromethyl-benzyl)-diphenylethyl-amino]-propan-1-ol(0.500 g, 1.12 mmol) in toluene (4 ml) at ambient temperature was added4-Hydroxy-benzaldehyde (0.213 g, 1.74 mmol) under Argon with stirring.The mixture was treated with polymer bound PPh₃ (0.594 g, 1.782 mmol).After 15 minutes of stirring, the mixture was treated with DIAD (0.273mL, 1.387 mmol) and was stirred at ambient temperature overnight. Thereaction mixture was filtered then concentrated, in-vacuo, to dryness.The oil was dissolved in DMSO and was purified via reverse-phase HPLC toyield the title compound (0.266 g, 43%); MS (ES+) m/e 553 [M+H]⁺.

b)(4-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-benzyl)-methyl-amine

A solution of4-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-benzaldehyde,(0.0443 g, 0.080 mmol) in dichloromethane (1 ml) and AcOH (00.1 mL), wastreated with CH₃NH₂ (40% solution in H₂O, 0.073 mmol) at ambienttemperature. To the mixture was added NaBH(OAc)₃ (0.017 g, 0.080 mmol),and the reaction was stirred overnight. The reaction mixture was thenconcentrated, in vacuo, to an oil, which was then dissolved in DMSO andpurified via reverse-phase HPLC to afford the title compound (0.007 g,15%); MS (ES+) m/e 568 [M+H]⁺.

The following Examples, 106-108, were prepared following the procedurefor Example 105 step b, with an alternate amine.

Character- Example Amine isation 106 (2-Chloro-3-trifluoromethyl-Dimethylamine MS(ES+) benzyl)-[3-(4-dimethylamino- m/e 582methyl-phenoxy)-propyl]-(2,2- [M + H]⁺ diphenyl-ethyl)-amine 107(2-Chloro-3-trifluoromethyl- Morpholine MS (ES+)benzyl)-(2,2-diphenyl-ethyl)-[3- m/e 624 (4-morpholin-4-ylmethyl- [M +H]⁺ phenoxy)-propyl]-amine 108 (2-Chloro-3-trifluoromethyl- N- MS (ES+)benzyl)-(2,2-diphenyl-ethyl)-{3- Methylpiperazine m/e 637[4-(4-methyl-piperazin-1- [M + H]⁺ ylmethyl)-phenoxy]-propyl}-amine

EXAMPLE 109(3-{3-[(Chloro-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-benzyl)-methyl-amine

a)3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-benzaldehyde

To a solution of3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propan-1-ol(0.500 g, 1.12 mmol) in toluene (4 ml) at ambient temperature was added3-Hydroxy-benzaldehyde (0.213 g, 1.74 mmol) under Argon with stirring.The mixture was treated with polymer bound PPh₃ (0.594 g, 1.782 mmol).After 15 minutes of stirring, the mixture was treated with DIAD (0.273mL, 1.387 mmol) and was stirred at ambient temperature overnight.

The reaction mixture was filtered then concentrated, in-vacuo, todryness. The oil was dissolved in DMSO and was purified viareverse-phase HPLC to yield the title compound (0.192 g, 31%); MS (ES+)m/e 553 [M+H]⁺.

b)(3-{3-[(Chloro-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-benzyl)-methyl-amine

A solution of3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-benzaldehyde,(0.032 g, 0.058 mmol) in dichloromethane (1 ml) and AcOH (0.1 mL), wastreated with CH₃NH₂ (40% solution in H₂O, 0.053 mmol) at ambienttemperature. To the mixture was added NaBH(OAc)₃ (0.0123 g, 0.058 mmol),and the reaction was stirred overnight. The reaction mixture was thenconcentrated, in vacuo, to an oil, which was then dissolved in DMSO andpurified via reverse-phase HPLC to afford the title compound (0.004 g,12%); MS (ES+) m/e 568 [M+H]⁺.

The following Examples, 110-113, were prepared following the procedurefor Example 109 step b, with an alternate amine.

Character- Example Amine isation 110 (2-Chloro-3-trifluoromethyl-Dimethylamine MS(ES+) benzyl)-[3-(3- m/e 582 dimethylaminomethyl- [M +H]⁺ phenoxy)-propyl]-(2,2- diphenyl-ethyl)-amine 111(2-Chloro-3-trifluoromethyl- Morpholine MS (ES+) benzyl)-(2,2-diphenyl-m/e 624 ethyl)-[3-(3-morpholin-4- [M + H]⁺ ylmethyl-phenoxy)-propyl]-amine 112 (2-Chloro-3-trifluoromethyl- N-Methylpiperazine MS (ES+)benzyl)-(2,2-diphenyl- m/e 637 ethyl)-{3-[3-(4-methyl- [M + H]⁺piperazin-1-ylmethyl)- phenoxy]-propyl}-amine 113 (3-{3-[(2-Chloro-3-Isopropylamine MS (ES+) trifluoromethyl-benzyl)- m/e 596diphenylethyl-amino]- [M + H]⁺ propoxy}-benzyl)-isopropyl- amine

EXAMPLE 114{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-4-trifluoromethyl-phenylamine

a) 2-Methoxy-4-nitrobenzotrifluoride

Equip a 2 L 3-necked flask with an oil bath, magnetic stirrer,thermocouple, condenser, and addition funnel vented into a causticscrubber. Charge the flask with 1-methyl-2-pyrrolidinone (NMP) (300 mL,2 volumes), 2-iodo-5-nitroanisole (145.2 g, 1.00 eq) and copper (I)iodide (14.8 g, 0.15 eq). With stirring, heat the reaction mixture to80-100° C. Charge the addition funnel with methyl fluorosulfonyldifluoroacetate (200 g, 132 mL, 2.05 eq) and add keeping temperaturebelow 110° C. The mixture is heated for ca. 2 hours then checked by LCto monitor for loss of starting material. The mixture is cooled below90° C. then water (1400 mL, 9.6 vol) is added and the bath heated to140° C. Product is collected by azeotropic distillation with a pot tempof 102° C. and head-temp of 90° C. Distillation is stopped when pot tempfalls below 101° C. Product is isolated by extraction into 5 volumestert-butyl methyl ether (TBME), washed with 5 volumes water, and used asa solution in the subsequent stage.

b) 2-Trifluoromethyl-5-nitroaniline

Equip a 1 L 3-necked flask with an oil bath, magnetic stirrer,thermocouple, and distillation apparatus under a stream of nitrogen (2mL/min). Charge the flask with2-methoxy-4-nitrobenzotrifluoride/tert-butyl methyl ether (TBME)solution from stage 1 and concentrate to 40% volume (using atmosphericpressure, oil bath at 80° C. Cool the solution below 40° C. and add1-methyl-2-pyrrolidinone (NMP) (250 mL, 4.8 volumes). Continuedistillation at oil bath temp of 80° C., stopping when no furtherdistillate is collected under vacuum. The mixture is cooled to below 40°C. then charge with sodium dihydrogen phosphate hydrate (50 g, 1.6 eq),water (25 g, 6.2 eq), then lithium chloride (50 g, 5.2 eq). The mixtureis heated to 130° C. for 16 hours then checked by LC to monitor for lossof starting material. The mixture is cooled below 30° C. then TBME (500mL, 10 vol) and a mixture of water and conc HCl (500 mL, 4:1 water: concHCl, 10 vol) is added. The aqueous layers are removed and re-extractedusing TBME (150 mL, 3 vol). The combined organics are rinsed with amixture of water and conc HCl (450 mL, 9:1 water:HCl, 9 vol). Thecombined organics are concentrated by distillation to 40% volume.Toluene (75 mL, 1.5 vol) is added and distillation continued. Upon nofurther collection, vacuum is applied to reduce remaining volume to 50%.Heptanes (500 mL, 10 vol) are added and the mixture heated to 90° C.then cooled slowly (8 h) to 25° C. The crystals are isolated byfiltration to give 33 g (68%) of an off-white solid.

c)(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(nitro-trifluoromethyl-phenoxy)-propyl]-amine

To a solution of 2-trifluoro-3-nitro-phenol (0.28 g, 1.3 mmol), polymerbound triphenylphosphine (0.82 g, 2.45 mmol, 3 mmol/g, Fluka Chemie),N-(2,2-diphenylethyl)-N-(3-hydroxy-propyl)-N-(2-chloro-3-trifluoromethyl-benzyl)amine(0.35 g, 1.54 mmol), and CH₂Cl₂ (15 mL), diisopropylazodicarboxylate(0.30 mL, 1.94 mmol) was added and the reaction mixture was stirredovernight. The mixture was then filtered, concentrated, and purified viacombiflash to yield the product as a yellow oil (0.69 g, 81%): MS(ES)m/e 637.2 [M+H]⁺.

d){3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-4-trifluoromethyl-phenylamine

A solution of(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(nitro-trifluoromethyl-phenoxy)-propyl]-amine(0.28 g, 1.3 mmol), Pd/C (10%) (0.10 g, 0.10 mmol), and MeOH (15 mL)(0.35 g, 1.54 mmol) was treated with H₂ (balloon pressure) overnight.The mixture was then filtered, concentrated, and purified via combiflashto yield the product as a yellow oil (0.12 g, 18%): MS(ES) m/e 607.2[M+H]⁺

EXAMPLE 115{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-4-methyl-phenylamine

a){3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-4-methyl-phenylcarbamic acid tert-butyl ester

Following the procedure of Example 114 except substituting(3-hydroxy-4-methyl-phenyl)-carbamic acid tert-butyl ester for2-trifluoro-3-nitro-phenol in part c, the title compound was obtained asa clear oil (100 mg, 17%): MS(ES) m/e 653.2 [M+H]⁺.

b){3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-4-methyl-phenylamine

To a solution of{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-4-methyl-phenylcarbamic acid tert-butyl ester (0.09 g, 0.14 mmol) and CH₂Cl₂ (2 mL),TFA (0.20 mL, 1.2 mmol) was added and the reaction mixture was stirredfor 1 h. The mixture was then poured into NaHCO₃, extracted with CH₂Cl₂,dried over Na₂SO₄, filtered, and concentrated to yield the product as ayellow oil (0.03 g, 39%): MS(ES) m/e 553.2 [M+H]⁺.

EXAMPLE 116 Ethanesulfonic acid(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-4-methyl-phenyl)-amidetrifluoroacetic acid salt

To a solution of{3-[(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-4-methyl-phenylamine(0.02 g, 0.036 mmol), pyridine (0.030 mL, 0.36 mmol), and CH₂Cl₂ (0.3mL), ethanesulfonyl chloride (0.02 mL, 0.20) mmol) was added and thereaction mixture was stirred overnight. The mixture was concentrated andpurified via preparative HPLC (TMC CombiPrep PDS, 75×30 mm, 25 mL/min,acetonitrile:H₂O:TFA, UV detection at 254 nm) to yield the product as ayellow oil (0.02 g, 86%): MS(ES) m/e 645.2 [M+H]⁺.

EXAMPLE 117 Propane-2-sulfonic acid(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-4-methyl-phenyl)-amidetrifluoroacetic acid salt

Following the procedure of Example 116 except substitutingisopropylsulfonyl chloride for ethanesulfonyl chloride, the titlecompound was obtained as a yellow oil (20 mg, 84%): MS(ES) m/e 659.0[M+H]⁺.

EXAMPLE 118 Methanesulfonic acid(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy)-4-methyl-phenyl)-amidetrifluoroacetic acid salt

Following the procedure of Example 116 except substitutingmethanesulfonyl chloride for ethanesulfonyl chloride, the title compoundwas obtained as a yellow oil (20 mg, 86%): MS(ES) m/e 631.2 [M+H]⁺.

EXAMPLE 119 2,2,2-Trifluoro-ethanesulfonic acid(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-4-methyl-phenyl)-amidetrifluoroacetic acid salt

Following the procedure of Example 116 except substituting2,2,2-trifluoro-ethanesulfonyl chloride for ethanesulfonyl chloride, thetitle compound was obtained as a yellow oil (22 mg, 87%): MS(ES) m/e669.2 [M+H]⁺.

EXAMPLE 120 Ethanesulfonic acid(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-phenyl)-amidetrifluoroacetic acid salt

a)(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-nitro-phenoxy)-propyl]-amine

Following the procedure of Example 114 except substituting3-nitro-phenol for 2-trifluoro-3-nitro-phenol in part c, the titlecompound was obtained as a clear oil (155 mg, 35%): MS(ES) m/e 568.6[M+H]⁺.

b)3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-phenylamine

Following the procedure of Example 114 except substituting(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-nitro-phenoxy)-propyl]-aminefor(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(nitro-trifluoromethyl-phenoxy)-propyl]-aminein part d, the title compound was obtained as a clear oil (125 mg, 91%):MS(ES) m/e 539.2 [M+H]⁺.

c) Ethanesulfonic acid(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-phenyl)-amide

Following the procedure of Example 116 except substituting3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-phenylaminefor{3-[(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-4-methyl-phenylamine,the title compound was obtained as a yellow oil (23 mg, 79%): MS(ES) m/e631.2 [M+H]⁺.

EXAMPLE 121 2,2,2-Trifluoro-ethanesulfonic acid(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-phenyl)-amidetrifluoroacetic acid salt

Following the procedure of Example 120 except substituting2,2,2-trifluoro-ethanesulfonyl chloride for ethanesulfonyl chloride, thetitle compound was obtained as a yellow oil (25 mg, 79%): MS(ES) m/e685.2 [M+H]⁺.

EXAMPLE 122N-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-phenyl)-1,1,1-trifluoro-methanesulfonamidetrifluoroacetic acid salt

Following the procedure of Example 120 except substitutingtrifluoro-methanesulfonyl chloride for ethanesulfonyl chloride in partc, the title compound was obtained as a yellow oil (18 mg, 58%): MS(ES)m/e 671.2 [M+H]⁺.

EXAMPLE 123 Propane-2-sulfonic acid(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-phenyl)-amidetrifluoroacetic acid salt

Following the procedure of Example 120 except substitutingisopropylsulfonyl chloride for ethanesulfonyl chlorde in part c, thetitle compound was obtained as a yellow oil (21 mg, 71%): MS(ES) m/e645.0 [M+H]⁺.

EXAMPLE 124{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-4-methoxy-phenylamine

a){3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-4-methoxy-phenylcarbamic acid tert-butyl ester

Following the procedure of Example 114 except(3-hydroxy-4-methoxy-phenyl)-carbamic acid tert-butyl ester (Charpiot,Brigitte,s et al, Bioorg. Med. Chem. Lett., 1998, 8, 2891-2896) for2-trifluoro-3-nitro-phenol in part e, the title compound was obtained asa clear oil (110 mg, 12%): MS(ES) m/e 669.0 [M+H]⁺.

b){3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-4-methoxy-phenylamine

To a solution of{3-[(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-4-methoxy-phenylcarbamic acid tert-butyl ester (0.05 g, 0.075 mmol) and CH₂Cl₂ (2 mL),TFA (0.20 mL, 1.2 mmol) was added and the reaction mixture was stirredfor 1 h. The mixture was then poured into NaHCO₃, extracted with CH₂Cl₂,dried over Na₂SO₄, filtered, and concentrated to yield the product as ayellow oil (0.03 g, 70%): MS(ES) m/e 569.4 [M+H]⁺.

EXAMPLE 125 Ethanesulfonic acid(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-4-methoxy-phenyl)-amidetrifluoroacetic acid salt

Following the procedure of Example 120 except substituting{3-[(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-4-methoxy-phenylaminefor3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-phenylaminein part c, the title compound was obtained as a yellow oil (21 mg, 71%):MS(ES) m/e 661.4 [M+H]⁺.

EXAMPLE 126(2-Chloro-3-trifluoromethyl-benzyl)-{3-[3-(2-morpholinyl-4-yl-ethyl)-phenoxy]-propyl}-((S)-2-phenyl-propylamine hydrochloride salt

a) (2-chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-amine

To a solution of (S)-(−)-2-phenyl propylamine (0.5 g, 3.7 mmol) in drydichloromethane (100 ml) was added acetic acid (2 drops) followed by2-chloro-3-trifluoromethylbenzaldehyde (1.1 g, 5.5 mmol) and sodiumtriacetoxyborohydride (1.5 g, 7.4 mmol). After the resulting mixture wasstirred for 1.5 h at room temperature, water was added to quench thereaction. The aqueous layer was extracted with ethyl acetate. Thecombined organic layers was washed with brine, dried over sodium sulfateand concentrated in vacuo. The crude mixture was purified by silica gelcolumn chromatograph using EtOAc:Hexane/25:75 as the eluant to give 0.55g (45% yield) of the title compound as an oil. MS m/e327.6 (M+H)⁺.

b)(3-{3-[[2-chloro-3-trifluoromethyl-benzyl](S-2-phenyl-propyl)amino]propoxy}-phenyl)aceticacid methyl ester

A solution of (3-{3-bromo-propoxy}-phenyl)acetic acid methyl ester (0.55g, 1.5 mmol) and(2-chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-amine (0.55 g,1.6 mmol) in acetonitrile (10 ml) was treated with solid potassiumcarbonate (0.4 g, 2.4 mmol). The reaction was heated to reflux andstirred for 48 h. Upon cooling to room temperature, the reaction wasfiltered through a pad of celite, washed with EtOAc, and the filtratewas concentrated in vacuo. The crude product was purified by columnchromatograph (EtOAc:Hexane/20:80) to give the title compound as an oil(0.6 g, 67%). MS m/e 534.6 (M+H)⁺.

c)2-(3-{3-[[2-chloro-3-trifluoromethyl-benzyl](S-2-phenyl-propyl)amino]propoxy}-phenyl)aceticacid

A solution of(3-{3-[[2-chloro-3-trifluoromethyl-benzyl](S-2-phenyl-propyl)amino]propoxy}-phenyl)aceticacid methyl ester (0.6 g, 1.1 mmol) in THF (9 ml) and water (6 ml) wasadded aqueous LiOH (1.0 N, 1.0 ml, 1.0 mmol). After stirring at roomtemperature for 2 h, additional LiOH (1.0 ml, 1.0 mmol) was added andstirring was continued for 2 h. The reaction was neutralized with AcOHand poured into water and ethyl acetate. The layers were separated andthe aqueous layer was extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over sodium sulfate andconcentrated in vacco. The crude mixture was purified by HPLC to givethe title compound as an oil (0.4 g, 75%). MS m/e 520.2 (M+H)⁺.

d)2-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-1-morpholin-4-yl-ethanone

To a solution of2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](S-2-phenyl-propyl)amino]propoxy}-phenyl)aceticacid (100 mg, 0.19 mmol) and morpholine (20 μl) in acetonitrile (20 ml)was added BOP reagent (88 mg, 0.20 mmol) followed by the addition oftriethyl amine (2 drops). The reaction mixture was stirred at roomtemperature overnight and concentrated under vacuum. The residue waspartitioned between EtOAc and 5% NaHCO₃. The combined organic layers wasdried over sodium sulfate and concentrated to give the title compound ascolorless oil (78 mg, 70%). MS m/e 589.2 (M+H)⁺.

e)(2-Chloro-3-trifluoromethyl-benzyl)-{3-[3-(2-morpholin-4-yl-ethyl)-phenoxy]-propyl}-((S)-2-phenyl-propylamine hydrochloride salt

To a solution of2-(3-{3-[(Chloro-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-1-morpholin-4-yl-ethanone(70 mg, 0.13 mmol) in toluene (20 ml) was added DIBAL (1.5M in toluene,0.69 ml) dropwise at 0° C. After the reaction mixture was stirred at 0°C. for an additional 30 min it was warmed up to room temperature andstirred over night. The reaction was quenched by adding methanol and theorganic layer was washed with water, brine and dried over sodiumsulfate. After concentration, the crude mixture was purified by HPLC(YMC CombiPrep ODS-A, 50×20 mm, 20 mL/min, A: acetonitrile B: water, A:60 to 100% during 10 min, UV detection at 254 nm) to give 35 mg (50%yield) of free amine of the title compound as an oil MS m/e575.2 (M+H)⁺.To a solution of the free amine in diethyl ether was added HCl indiethyl ether (1.0M) to precipitate the amine salt. The suspension wasfiltered and dried to give the title compound as a white solid.

EXAMPLE 127(2-Chloro-3-trifluoromethyl-benzyl)-{3-[3-(2-ethylamino-ethyl)-phenoxy]-propyl}-((S)-2-phenyl-propyl)-aminehydrochloride salt

Following the procedure of Example 126 (a-e) except substitutingethylamine for morpholine in step d, the title compound was obtained asa white solid (35 mg, 45%). MS m/e 533.2 (M+H)⁺.

EXAMPLE 128(3-{(R)-3-[(2-Chloro-3-trifluoromethyl-benzyl)-(S)-2-phenyl-propyl)-amino]-butoxy}-phenyl)-aceticacid hydrochloride salt

a) (S)-[3-(3-Hydroxy-butoxy)-phenyl]-acetic acid methyl ester

To a stirring solution of (3-hydroxy-phenyl)-acetic acid methyl ester(0.93 g, 0.0056 mole) and toluene-4-sulfonic acid-(S)-3-hydroxy-butylester (1.5 g, 0.0061 mole) in anhydrous DMF (10 mL) was added Cs₂CO₃(2.0 g, 0.006 mole). The reaction was heated to 100° C. and stirred for4 hours. The mixture was cooled to RT and filtered. The filtrate waspoured into H₂O (50 mL) and extracted three times with EtOAc. Thecombined organic layers were dried over sodium sulfate, filtered, andconcentrated. The crude product was subjected to column chromatographyover silica gel (silica gel 60, EM Science) using 30% EtOAc:hexane aseluent to afford 0.59 g (44% yield) of the title compound as an oil: MS(ESI) 239.0 (M+H⁺).

b) (S)-{3-[3-(Toluene-4-sulfonyloxy)-butoxy]-phenyl}-acetic acid methylester

To a stirring solution of (S)-[3-(3-hydroxy-butoxy)-phenyl]-acetic acidmethyl ester (589 mg, 2.47 mmol) and triethylamine (376 mg, 3.71 mmol)in dichloromethane (10 mL) at 0° C. was added p-toluenesulfonyl chloride(944 mg, 4.95 mmol). The reaction was then stirred at RT for 30 min. andrefluxed overnight. The reaction mixture was poured into H₂O (40 mL) andextracted three times with dichloromethane. The combined organicextracts were dried over sodium sulfate, filtered, and concentrated. Thecrude product was purified by column chromatography over silica gel(silica gel 60, EM Science) using 15% EtOAc:hexane as eluent to afford0.61 g (63% yield) of the title compound as an oil: MS (ESI) (M+H⁺).

c) {3-[(R)-3-((S)-2-Phenyl-propylamino)-butoxy]-phenyl}-acetic acidmethyl ester

A solution of {3-[(S)-3-(Toluene-4-sulfonyloxy)-butoxy]-phenyl}-aceticacid methyl ester (0.2 g, 0.51 mmol) and (S)-2-Phenyl-propylamine (0.19,0.77 mmol) in acetonitrile (30 ml) was treated with solid potassiumcarbonate (0.149, 1.02 mmol). The reaction was heated to reflux andstirred for six days. Upon cooling to room temperature, the reaction wasfiltered through a pad of celite, washed with EtOAc, and the filtratewas concentrated in vacuo. The crude product was purified by columnchromatograph (EtOAc:Hexane/20:80) to give the title compound as an oil(0.12 g, 40%). MS m/e 356.6 (M+H)⁺.

d)(3-{(R)-3-[(2-Chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-amino]-butoxy}-phenyl)-aceticacid methyl ester

To a solution of{3-[(R)-3-((S)-2-Phenyl-propylamino)-butoxy]-phenyl}-acetic acid methylester (0.12 g, 0.34 mmol) in dry dichloromethane was added acetic acidfollowed by 2-chloro-3-trifluoromethylbenzaldehyde (0.1 g, 0.51 mmol)and sodium triacetoxyborohydride (0.149, 0.68 mmol). After the resultingmixture was stirred at room temperature overnight water was added toquench the reaction. The aqueous layer was extracted with ethyl acetate.The combined organic layers was washed with brine, dried over sodiumsulfate and concentrated in vacco. The crude mixture was purified bysilica gel column chromatography using EtOAc:Hexane/25:75 as the eluentto give 50 mg (40% yield) of the title compound as an oil MS m/e 548.4(M+H)⁺.

e)(3-{(R)-3-[(2-Chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-amino]-butoxy}-phenyl)-aceticacid hydrochloride salt

A solution of compound(3-{(R)-3-[(2-Chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-amino]-butoxy}-phenyl)-aceticacid methyl ester (50 mg, 0.1 mmol) in THF (9 ml) and water (6 ml) wastreated with aqueous LiOH (1.0 N, 1.0 ml, 1.0 mmol). After stirring atroom temperature for 2 h, additional LiOH (1.0 ml, 1.0 mmol) was addedand stirring was continued for 2 h. The reaction was neutralized withAcOH and poured into water and ethyl acetate. The aqueous layer wasextracted with EtOAc and the combined organic layers were washed withbrine, dried over sodium sulfate and concentrated in vacco. The crudemixture was purified by HPLC (YMC CombiPrep ODS-A, 50×20 mm, 20 mL/min,A: acetonitrile B: water, A: 60 to 100% during 10 min, v detection at254 nm) to give the free acid of title compound as an oil (40 mg, 75%).MS m/e 534.2 (M+H)⁺. To a solution of the free amine in diethyl etherwas added HCl in diethyl ether (1.0M) to precipitate the HCl salt. Thesuspension was filtered and dried to give the title compound as a whitesolid.

EXAMPLE 129(3-{(S)-3-[(2-Chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-amino]-butoxy}-phenyl)-aceticacid hydrochloride salt

Following the procedure of Example 128 except toluene-4-sulfonicacid-(R)-3-hydroxy-butyl ester was used instead of toluene-4-sulfonicacid-(S)-3-hydroxy-butyl ester in step a, the title compound wasobtained as a white solid (35 mg, 30%). MS (ESI): 534.2 (M+H)⁺

EXAMPLE 1302-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-ethanolhydrochloride salt

To a solution of(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)(S)-2-phenyl-propyl)-amino]-butoxy}-phenyl)-aceticacid methyl ester (Example 10c, 90 mg, 1.7 mmol) in THF (40 ml) wasadded LiAlH₄ (0.4 ml, 1.0M in THF). The reaction mixture was heated toreflux for 1.5 h. After the mixture was cooled to room temperature waterwas added to quench the reaction which was then filtered. The filtratewas concentrated and the crude product was purified by silica gel columnchromatograph using EtOAc:Hexane/25:75 as the eluent to give 30 mg (40%yield) of free amine of the title compound as an oil MS m/e506.4 (M+H)⁺.To a solution of the free amine in diethyl ether was added HCl indiethyl ether (1.0M) to precipitate HCl salt. The suspension wasfiltered and dried to give the title compound as a white solid.

EXAMPLE 1312-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-2-methyl-propionicacid hydrochloride salt

a)(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-aceticacid methyl ester

To a solution of(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-aceticacid (Example 10, 0.5 g, 3.7 mmol) in methanol (300 ml) was addedconcentrated hydrochloric acid (10 ml). After the resulting mixture washeated to reflux for 2 h solvent was removed under vacuum. The residuewas dissolved in water and neutralized to pH=7. The aqueous layer wasextracted with ethyl acetate. The combined organic layers were washedwith saturated sodium bicarbonate, brine, dried over sodium sulfate, andconcentrated in vacco to give the title compound as colorless oil (0.5g, 90%). MS m/e 534.6 (M+H)⁺.

b)2-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-2-methyl-propionicacid methyl ester

To a solution of(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-aceticacid methyl ester (70 mg, 0.12 mmol) in dry THF (50 ml) was addedlithium diisopropyl amide (1.7 ml, 1.2 mmol) dropwise when it was cooledto −78° C. After the reaction mixture was stirred at −78° C. foradditional 1 h iodoethane (0.4 ml) was added. The reaction was warmed toroom temperature over 4 h followed by quenching with saturated ammoniumchloride (10 ml). Solvent was removed and the residue was partitionedbetween water and ethyl acetate. The combined organic layers were washedwith brine, dried over sodium sulfate and concentrated under vacuum. Theresidue was purified by silica gel column chromatograph(EtOAc:Hexane/20:80) to give the title compound as an oil (37.2 mg,50%). MS m/e 562.2 (M+H)⁺.

c)2-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-2-methyl-propionicacid hydrochloride salt

A solution of2-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-2-methyl-propionicacid methyl ester (30 mg, 0.05 mmol) in DMF (9 ml) was treated with LiCl(20 mg, 0.46 mmol). The resulting reaction mixture was heated to refluxovernight and concentrated under vacuum. The crude product was purifiedby HPLC (YMC CombiPrep ODS-A, 50×20 mm, 20 mL/min, A: acetonitrile B:water, A: 60 to 100% during 10 min, UV detection at 254 nm) to give thetitle compound free amine as an oil (15 mg, 45%). MS m/e 548.2(M+H)⁺. Toa solution of the free amine in diethyl ether was added HCl in diethylether (1.0M) to precipitate the amine salt. The suspension was filteredand dried to give the title compound as a white solid.

EXAMPLE 1322-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-((R)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-2-methyl-propionicacid hydrochloride salt

Following the procedure of Example 131 except substituting(3-{3-[(Chloro-trifluoromethyl-benzyl)-((R)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-aceticacid (Example 11) for(3-(3-[(2-Chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-aceticacid in step a, the title compound was obtained as a white solid (25 mg,35%). MS (ESI): 548.2 (M+H)⁺.

EXAMPLE 133(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2-thiophen-3-yl-propyl)-amino]-propoxy}-phenyl)-aceticacid hydrochloride salt

a) 2-thiophen-3-yl-propionaldehyde

A solution of methoxymethyldiphenyl phosphonium chloride (4 g, 11.9mmol) in anhydrous ethanol (50 ml) was cooled to 0° C. and sodiumethoxide (0.8 g, 8.25 mmol) was added. After the mixture had warmed toroom temperature, 1-thiophen-3-yl-ethanone (0.7 g, 5.9 mmol) was addedand the reaction mixture was heated to 120° C. for 30 min in Microwave.The mixture was filtered and the filtrate was concentrated. The crudeproduct was purified by silica gel column chromatograph usingEtOAc:Hexane/20:80 as the eluent to give 0.5 g (54.5% yield) 3-((E orZ)-2-methoxy-1-methyl-vinyl)-thiophene. The solution of 3-((E orZ)-2-methoxy-1-methyl-vinyl)-thiophene in THF:HCl: H₂O (10 ml total,9:0.5:1) was heated to 150° C. for 30 min in microwave. After themixture was concentrated the residue was partitioned between EtOAc andwater. The combined organic layers were washed with sodium bicarbonate,water, brine, dried over sodium sulfate and concentrated to give thetitle compound as an oil 250 mg (30%).

b){3-[3-(2-chloro-3-trifluoromethyl-benzylamino)-propoxy]-phenyl}-aceticacid methyl ester

A solution of [3-(3-bromo-propoxy)-phenyl]-acetic acid methyl ester (1.5g, 5.26 mmol) and 2-chloro-3-trifluoromethyl-benzylamine (1 g, 4.77mmol) in acetonitrile (300 ml) was treated with solid potassiumcarbonate (0.79 g, 5.74 mmol). The reaction was heated to reflux andstirred overnight. Upon cooling to room temperature, the reaction wasfiltered through a pad of celite, washed with EtOAc, and the filtratewas concentrated in vacuo. The crude product was purified by columnchromatograph (EtOAc:Hexane/30:90) to give the title compound as an oil(1.5 g, 50%). MS m/e 402.2 (M+H)⁺.

c)(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2-thiophen-3-yl-propyl)-amino]-propoxy}-phenyl)-aceticacid methyl ester

To a solution of{3-[3-(2-chloro-3-trifluoromethyl-benzylamino)-propoxy]-phenyl}-aceticacid methyl ester (70 mg, 0.17 mmol) in dry dichloromethane (20 ml) wasadded acetic acid (2 drops) followed by 2-thiophen-3-yl-propionaldehyde(26 mg, 0.19 mmol) and sodium triacetoxyborohydride (72 mg, 0.34 mmol).After the resulting mixture was stirred at room temperature overnight,water was added to quench the reaction. The aqueous layer was extractedwith ethyl acetate. The combined organic layers was washed with brine,dried over sodium sulfate and concentrated in vacco. The crude mixturewas purified by HPLC (YMC CombiPrep ODS-A, 50×20 mm, 20 mL/min, A:acetonitrile B: water, A: 60 to 100% during 10 min, UV detection at 254nm) to give 50 mg (32% yield) of the title compound as an oil MS m/e541.4 (M+H)⁺.

d)(3-{3-[(Chloro-trifluoromethyl-benzyl)-(2-thiophen-3-yl-propyl)-amino]-propoxy}-phenyl)-aceticacid hydrochloride salt

A solution of(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2-thiophen-3-yl-propyl)-amino]-propoxy}-phenyl)-aceticacid methyl ester (30 mg, 0.07 mmol) in THF (9 ml) and water (6 ml) wastreated with aqueous LiOH (1.0 N, 1.0 ml, 1.0 mmol). After stirring atroom temperature for 2 h, additional LiOH (1.0 ml, 1.0 mmol) was addedand stirring was continued for 2 h. The reaction was neutralized withAcOH and poured into water and ethyl acetate. The aqueous layer wasextracted with EtOAc and the combined organic layers were washed withbrine, dried over sodium sulfate and concentrated in vacco. The crudemixture was purified by HPLC (YMC CombiPrep ODS-A, 50×20 mm, 20 mL/min,A: acetonitrile B: water, A: 60 to 100% during 10 min, UV detection at254 nm) to give the free acid of title compound as an oil (25 mg, 75%).MS m/e 527.2 (M+H)⁺. To a solution of the free amine in diethyl etherwas added HCl in diethyl ether (1.0M) to precipitate HCl salt. Thesuspension was filtered and dried to give the title compound as a whitesolid.

EXAMPLE 1342-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2-thiophen-3-yl-propyl)-amino]-propoxy}-phenyl)-ethanolhydrochloride salt

a) The procedure of Example 131 (a-c) was used to make(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2-thiophen-3-yl-propyl)-amino]-propoxy}-phenyl)-aceticacid methyl ester b)2-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2-thiophen-3-yl-propyl)-amino]-propoxy}-phenyl)-ethanolhydrochloride salt

To a solution of(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2-thiophen-3-yl-propyl)-amino]-propoxy}-phenyl)-aceticacid methyl ester (50 mg, 0.1 mmol) in THF (20 ml) was added LiAlH₄ (0.2ml, 11.0M in diethyl ether). After the reaction mixture was heated toreflux for 4 h it was cooled down to room temperature followed by theaddition of NaOH (1 ml, 2N) to quench the reaction. The reaction mixturewas filtered and the filtrate was concentrated. The crude product waspurified by HPLC (YMC CombiPrep ODS-A, 50×20 mm, 20 mL/min, A:acetonitrile B: water, A: 60 to 100% during 10 min, UV detection at 254nm) to give the free amine of the title compound as an oil (25 mg, 40%).MS m/e 512.2 (M+H)⁺. To a solution of the free amine in diethyl etherwas added HCl in diethyl ether (1.0M) to precipitate the HCl salt Thesuspension was filtered and dried to give the title compound as a whitesolid.

EXAMPLE 135(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2-thiophen-2-yl-propyl)-amino]-propoxy}-phenyl)-aceticacid hydrochloride salt

a) 2-thiophen-2-yl-propionaldehyde

To a solution of diethylisocyanomethylphosphonate in diethyl ether (40ml) was added butyl lithium (6.9 ml, 1.6M in hexane) dropwise at −60° C.After the reaction mixture was stirred at −60° C. for additional 15 mina solution of 2-acetylthiophene (1.26 g, 10 mmol) in diethyl ether (10ml) was added at the same temperature. The reaction mixture was warmedup to 0° C. and was stirred for 1.5 h. Concentrated HCl (15 ml) wasadded at 0° C. and then ice bath was removed. After the resultingmixture was stirred at room temperature overnight it was poured to coldwater (20 ml). The organic layer was washed with water, sat. sodiumbicarbonate, brine, dried over sodium sulfate and concentrated. Thecrude product was used in the next step without purification.

b) (2-chloro-3-trifluoromethyl-benzyl)-(2-thiophen-2-yl-propyl)-amine

To a solution of 2-thiophen-2-yl-propionaldehyde (100 mg, 0.7 mmol) indry dichloromethane (20 ml) was added2-chloro-3-trifluoromethyl-benzylamine (30 mg, 0.14 mmol) followed bythe addition of sodium triacetoxyborohydride (60.5 mg, 0.28 mmol). Afterthe resulting mixture was stirred at room temperature overnight waterwas added to quench the reaction. The aqueous layer was extracted withethyl acetate. The combined organic layers was washed with brine, driedover sodium sulfate and concentrated in vacco. The crude mixture waspurified by silica gel column chromatograph using EtOAc:Hexane/25:75 asthe eluent to give 50 mg (40% yield) of the title compound as an oil. MSm/e 334.4 (M+H)⁺.

c)(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-(2-thiophen-2-yl-propyl)-amino]-propoxy}-phenyl)-aceticacid methyl ester

A solution of (3-{3-bromo-propoxy}-phenyl)acetic acid methyl ester (41mg, 0.14 mmol) and(2-chloro-3-trifluoromethyl-benzyl)-(2-thiophen-2-yl-propyl)-amine (50mg, 10.14 mmol) in acetonitrile (10 ml) was treated with solid potassiumcarbonate (24.9 mg, 0.18 mmol). The reaction was heated to reflux andstirred for 48 h. Upon cooling to room temperature, the reaction wasfiltered through a pad of celite, washed with EtOAc, and the filtratewas concentrated in vacuo. The crude product was purified by columnchromatograph (EtOAc:Hexane/20:80) to give the title compound as an oil(25 mg, 30%). MS m/e 540.6 (M+H)⁺.

d)(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2-thiophen-2-yl-propyl)-amino]-propoxy}-phenyl)-aceticacid hydrochloride salt

A solution of(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-(2-thiophen-2-yl-propyl)-amino]-propoxy}-phenyl)-aceticacid methyl ester (25 mg, 0.05 mmol) in THF (9 ml) and water (6 ml) wastreated with aqueous LiOH (1.0 N, 0.29 ml, 1.0 mmol). After stirring atroom temperature for 2 h, additional LiOH (0.29 ml, 1.0 mmol) was addedand stirring was continued for 2 h. The reaction was neutralized withAcOH and poured into water and ethyl acetate. The layers were separatedand the aqueous layer was extracted with EtOAc. The combined organiclayers were washed with brine, dried over sodium sulfate andconcentrated in vacco. The crude mixture was purified by HPLC to givethe free amine of title compound as an oil (15 mg, 58%). MS m/e 520.2(M+H)⁺. To a solution of the free amine in diethyl ether was added HClin diethyl ether (1.0M) to precipitate HCl salt The suspension wasfiltered and dried to give the title compound as a white solid.

EXAMPLE 136(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2-pyridin-2-yl-propyl)-amino]-propoxy}-phenyl)-aceticacid hydrochloride salt

Following the procedure of Example 133 a-d, except substituting1-pyridin-2-yl-ethanone for 2-acetylthiophene in step a, the titlecompound was obtained as a white solid (15 mg, 50%). MS (ESI): 522.0(M+H)⁺

EXAMPLE 137[3-(3-{(2-Chloro-3-trifluoromethyl-benzyl)-[2-(4-methyl-pyridin-2-yl)-propyl]-amino}-propoxy)-phenyl]-aceticacid hydrochloride salt

Following the procedure of Example 133 a-d, except substituting1-(4-methyl-pyridin-2-yl)-ethanone for 2-acetylthiophene in step a, thetitle compound was obtained as a white solid (15 mg, 50%). MS (ESI):535.0 (M+H)⁺.

EXAMPLE 138[3-(3-{(2-Chloro-3-trifluoromethyl-benzyl)-[3,3,3-trifluoro-2-(1H-pyrrol-2-yl)-propyl]-amino}-propoxy)-phenyl]-aceticacid hydrochloride salt

Following the procedure of Example 126 a-c, except substituting3,3,3-trifluoro-2-(1H-pyrrol-2-yl)-propylamine for (S)-(−)-2-phenylpropylamine in step a, the title compound was obtained as a white solid(15 mg, 50%). MS (ESI): 563.6 (M+H)⁺

Intermediate 12-(3-{3-[(2-Chloro-3-(trifluoromethyl)-benzyl)-(2,2-diphenylethyl)-amino]-propoxy}phenyl)-1-morpholin-4-yl-ethanonehydrochloride salt

a) Methyl [3-(3-bromopropoxy)phenyl]acetate

A solution of methyl 3-hydroxyphenylacetate (11.3 g, 0.068 mole) in 300mL of anhydrous toluene was treated with 3-bromopropanol (12.2 g, 0.088mole). Polymer bound triphenylphosphine (36.0 g, 0.108 mole, 3 mmol/g,Fluka Chemie) was then added, and the mixture reacted for 15 minutes.The reaction mixture was then cooled to 0° C. anddiisopropylazodicarboxylate (16.9 g, 0.084 mol) was added in a dropwisefashion. After stirring at room temperature overnight, the crudereaction mixture was filtered and the solid washed with 100 mL toluene.After concentration of the filtrate in vacuo, the crude product waspurified by column chromatography over silica gel (silica gel 60, EMScience) using 15% EtOAc:hexane as eluent to afford 15.8 g (81% yield)of the title compound as an oil:

¹H NMR (CDCl₃, 400 MHz) δ 7.23-7.19 (m, 1 H), 6.85-6.7 (m, 3), 4.09-4.06(t, 2 H. J=5.8), 3.67 (s, 3 H), 3.67-3.56 (m, 4 H), 2.32-2.26 (p, 2 H,J=6.0); MS (ESP+) m/e 288 (MH⁺); TLC (hexanes:EtOAc/3:1) R_(f)=0.68.Anal. (C₁₂H₁₅O₃Br) C, H, N.

b) N-[2-Chloro-3-(trifluoromethyl)benzyl]-N-(2,2-diphenylethyl)amine

A solution of 2,2-diphenethylamine (10.0 g, 50.7 mmol) and2-chloro-3-trifluoromethylbenzaldehyde (10.5 g, 50.7 mmol) in 80 mL ofmethanol and 40 mL of trimethylorthoformate was stirred at roomtemperature for 15 hours whereupon polymer-supported borohydride resin(20.3 g, 55.8 mmol, 2.5 mmol/g, Aldrich) was added in one portion. Afterstirring at room temperature for 24 h, the reaction was filtered and thefiltrate was concentrated in vacuo. The crude product was purified bycolumn chromatography over silica gel (silica gel 60, EM Science) usingEtOAc:hexane/40:60 with 1% NH₄OH as the eluent to give 11.2 g (57%yield) of the title compound as an oil: ¹H NMR (CDCl₃, 400 MHz) δ 7.57(d, 1 H, J=8.0), 7.52 (d, 1 H, J=7.6), 7.32-7.15 (m, 11 H), 4.20 (t, 1H, J=7.6), 3.94 (s, 2 H), 3.22 (d, 2 H, J=7.6); HPLC (Waters symmetryshield, RPq 3.5 micron, 2.1×30 mm, 85:15/H₂O:CH₃CN with 0.1% HCOOH to100% CH₃CN after 4 min, flow rate=0.8 mL/min) t_(R)=2.39 min; MS (ESP+)m/e 390 (MH⁺); TLC (hexanes:EtOAc/4:1) R_(f)=0.42.

c) Methyl(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]propoxy}phenyl)acetate

A solution of methyl [3-(3-bromopropoxy)phenyl]acetate (1.0 g, 3.48mmole) and N-[2-chloro-3-(trifluoromethyl)benzyl]-2,2-diphenylethanamine(1.63 g, 4.18 mmole) in 20 mL of acetonitrile was treated with potassiumcarbonate (0.72 g, 5.2 mmol). The reaction mixture was heated to refluxand stirred for 4 days. The reaction mixture was filtered, and thefiltrate was concentrated in vacuo. The crude product was purified byflash chromatography (silica gel cartridge, Biotage 32-63 um, 60A) with10% EtOAc:hexanes as the eluent to afford 1.69 g (81% yield) of thetitle compound as a viscous oil: ¹H NMR (CDCl₃, 400 MHz) δ 7.46-7.44 (d,1 H, J=7.7), 7.25-7.14 (m, 12 H), 6.91-6.84 (m, 2 H), 6.66-6.62 (m, 2H), 4.15-4.09 (t, 1 H. J=7.6), 3.78 (s, 1 H), 3.69-3.66 (m, 5 H),3.59(S, 2 H), 3.15-3.13 (d, 2 H, J=7.7), 2.72-2.68 (t, 2 H, J=6.6),1.87-1.80 (m, 2 H); MS (ESP+) m/e 597 (MH⁺); TLC (hexanes:EtOAc/9:1)R_(f)=0.36.

d)2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]propoxy}-phenyl)aceticacid hydrochloride salt

A solution of methyl(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]propoxy}phenyl)acetate(113 mg, 0.19 mmol) in 1.5 mL of tetrahydrofuran and 1 mL of water wastreated with 1 N aqueous LiOH (0.29 mL, 0.29 mmol). After stirring atroom temperature for 2 hours, additional 1N aqueous LiOH (0.29 mL, 0.29mmol) was added and stirring was continued for 2 hours. The reaction wasneutralized with AcOH (66 μL, 0.58 mmol) and poured into H₂O/EtOAc. Thelayers were separated and the aqueous layer was extracted with EtOAc(3×). The combined organic layers were washed with brine (1×), driedover magnesium sulfate, filtered, and concentrated in vacuo. The crudematerial was purified by preparative thin layer chromatography (silicagel, 1 mm plates, Merck 20×20 cm silica gel 60 F₂₅₄) eluting withCH₂Cl₂:MeOH (95:5) to afford an oil. The oil was dissolved in Et₂O andacidified with excess HCl/Et₂O. The reaction was concentrated in vacuoand dried under reduced pressure to give 65 mg (56% yield) of the titlecompound as a white solid: H NMR (C₅D₅N, 400 MHz) δ 7.60-7.05 (m, 15 H),7.01 (t, 1 H, J=7.6), 6.84 (dd, 1 H, J=8.4, 2.4), 4.32 (t, 1 H, J=7.6),3.89 (s, 2 H), 3.77 (s, 2 H), 3.71 (t, 2 H, J=5.6), 3.16 (d, 2 H,J=7.6), 2.65 (t, 2 H, J=6.4), 1.88-1.78 (m, 2 H).

e)2-(3-{3-[(2-Chloro-3-(trifluoromethyl)-benzyl)-(2,2-diphenylethyl)-amino]-propoxy}phenyl)-1-morpholin-4-yl-ethanonehydrochloride salt

2-{3-[[2-chloro-3-(trifluoromethyl)benzyl)(2,2-diphenylethyl)-amino]-propoxy}-phenylacetic acid (50 mg, 0.086 mmole) and morpholine (8.7 mg, 0.10 mmole)were dissolved in CH₃CN (2 ml). BOP reagent (44 mg, 0.10 mmole) wasadded followed by Et₃N (20 mg, 0.20 mmole). The resultant mixture wasstirred at room temperature for 2 h. The mixture was concentrated underreduced pressure. The residue was partitioned between EtOAc and aqueousNa₂CO₃ (5%) solution. The organic layer was separated, dried over MgSO₄and concentrated. In cases where the product required furtherpurification, a preparative Gilson HPLC was used (YMC CombiPrep ODS-A,50×20 mm, 20 m/min, 30-90% CH₃CN over 15 minutes). The HCl salt was madeby adding HCl (in ether) to an ether solution of the product and thenevaporation of the solvent to give a yellow solid (32 mg, 54%). MS(ES)m/e 651.2 [M+H]⁺.

Following the procedure from Intermediate 1, the following amides wereprepared:

In. Amine Compound Name M/S 2 4-methyl- 2-(3-{3-[(2-Chloro-3-(trifluoro-664.2 piperazine methyl)-benzyl)-(2,2-diphenylethyl)- (M + H⁺)amino]-propoxy}phenyl)-1-(4- methyl-piperazin-1-yl)-ethanonehydrochloride salt 3 methylamine 2-(3-{3-[(2-Chloro-3-(trifluoro- 595.2methyl)-benzyl)-(2,2-diphenylethyl)- (M + H⁺)amino]-propoxy}phenyl)-N-methyl- acetamide hydrochloride salt 4(1H-Imidazol-2- 2-(3-{3-[(2-chloro-3-trifluoromethyl- 661.4yl)-methylamine benzyl)-diphenylethyl-amino]- (M⁺)propoxy}-phenyl)-N-(1H-imidazol-2- ylmethyl)-acetamide hydrochloridesalt 5 (5-Bromo- N-(5-Bromo-thiophen-2-ylmethyl)-2- 755.2thiophen-2-yl)- (3-{3-[(2-chloro-3-trifluoromethyl- (M − H)⁺ methylaminebenzyl)-diphenylethyl-amino]- propoxy}-phenyl)-acetamide hydrochloridesalt 6 Thiophen-2-yl- 2-(3-{3-[(2-chloro-3-trifluoromethyl- 677.2methylamine benzyl)-diphenylethyl-amino]- (M⁺)propoxy}-phenyl)-N-thiophen-2- ylmethyl-acetamide hydrochloride salt 7ethylamine 2-(3-{3-[(2-Chloro-3-(trifluoro- 609.2methyl)-benzyl)-(2,2-diphenylethyl)- (M + H⁺)amino]-propoxy}phenyl)-N-ethyl- acetamide hydrochloride salt 8dimethylamine 2-(3-{3-[(2-Chloro-3-(trifluoro- 609.4methyl)-benzyl)-(2,2-diphenylethyl)- (M + H⁺)amino]-propoxy}phenyl)-N,N-di- methyl-acetamide hydrochloride salt 9pyrrolidine 2-(3-{3-[(2-Chloro-3-(trifluoro- 635.4methyl)-benzyl)-(2,2-diphenylethyl)- (M + H⁺) amino]-propoxy}phenyl)-1-pyrrolidin-1-yl-ethanone hydrochloride salt

Intermediate 10(R)-2-(3-{3-[(2-Chloro-3-trifluoromethyl)-benzyl)-(2,2-diphenylethyl)-amino]-2-methyl-propoxy}phenyl)-1-morpholin-4-yl-ethanonehydrochloride salt

a) (3-Hydroxy-phenyl)-acetic acid methyl ester

To a stirring solution of (3-hydroxy-phenyl)-acetic acid (4.3 g, 0.028mole) in methanol (30 mL) was added H₂SO₄ (1 mL) and the mixture washeated to reflux for 2 hours. The solvent was removed, the residue waswashed with H₂O, and extracted three times with EtOAc (ethyl acetate).The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated to give 4.7 g (99% yield) of the title compound as an oil.MS (ESI) 167.0(M+H⁺).

b) (S)-[3-(2-Methyl-3-bromopropoxy)phenyl]acetic acid methyl ester

To a stirring solution of (3-hydroxy-phenyl)-acetic acid methyl ester(0.75 g, 0.0045 mole) in anhydrous toluene (30 mL) was added(S)-(+)-3-bromo-2-methyl-1-propanol (0.90 g, 0.0059 mole). Polymer boundtriphenylphosphine (2.4 g, 0.0072 mole, 3 mmol/g, Fluka Chemie) was thenadded, and the mixture was stirred for 15 minutes. The reaction mixturewas then cooled to 0° C. and diisopropylazodicarboxylate (1.1 g, 0.00560mole) was added In a dropwise fashion. After stirring at roomtemperature overnight, the crude reaction mixture was filtered, and thesolid washed with toluene. After concentration of the filtrate in vacuo,the crude product was purified by column chromatography over silica gel(silica gel 60, EM Science) using 15% EtOAc:hexane as eluent to afford0.86 g (63% yield) of the title compound as an oil: MS (ESI) 303.0(M+2H⁺).

c) N-(2,2-Diphenylethyl)-N-(2-chloro-3-trifluoromethyl-benzyl)amine

To a stirring solution of 2,2-diphenethylamine (2.0 g, 0.010 mole) and2-chloro-3-trifluoromethylbenzaldehyde (2.33 g, 0.011 mole) indichloromethane (20 mL) was added sodium triacetoxyborohydride (2.36 g,0.011 mole) and acetic acid (2.0 mL). The reaction mixture was stirredovernight Solvent was removed, the residue was washed with saturatedNaHCO₃, and extracted three times with EtOAc. The organic extracts weredried over Na₂SO₄, filtered, and concentrated. The crude mixture wassubjected to column chromatography over silica gel (silica gel 60, EMScience) using 30% EtOAc:hexane as eluent to afford 3.0 g (76% yield) ofthe title compound as a yellow oil: MS (ESI) 390.0 (M+H⁺).

d)(R)-2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]-2-methyl-propoxy}-phenyl)aceticacid methyl ester

To a stirring solution of (S)-[3-(2-methyl-3-bromopropoxy)phenyl]aceticacid methyl ester (100 mg, 0.33 mmol) andN-(2,2-diphenylethyl)-N-(2-chloro-3-trifluoromethyl)amine (130 mg, 0.33mmol) in acetonitrile (5 mL) was added solid K₂CO₃ (138 mg, 1.0 mmol)and Nal (149 mg, 1.0 mmol). The reaction was heated to reflux andstirred overnight Upon cooling to room temperature, the reaction wasfiltered, washed with acetonitrile, and the filtrate was concentrated.The crude product was purified by preparative HPLC (TMC CombiPrep PDS,75×30 mm, 25 mL/min, acetonitrile:H₂O, UV detection at 254 nm) to give29 mg (14% yield) of title compound as a viscous oil. MS(ESI) 610.2(M⁺).

e)(R)-2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]-2-methyl-propoxy}-phenyl)aceticacid hydrochloride salt

To a stirring solution of(R)-2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]-2-methyl-propoxy}-phenyl)aceticacid methyl ester (22 mg, 0.0361 mmol) in THF (0.75 ml) and water (0.25ml) was treated with LiOH (3.0 mg, 0.072 mmol). The reaction mixture wasstirred overnight at RT. The reaction mixture was concentrated and 3 NHCl (aq.) was added until the pH was less than two. The aqueous layerwas extracted three times with EtOAc, the combined organic layers weredried over sodium sulfate, filtered, and concentrated. The resultingamine/carboxylic acid was dissolved in Et₂O (diethylether) and acidifiedwith 1.0 M HCl/Et₂O. The reaction mixture was concentrated in vacuo anddried under reduced pressure to give 18 mg (78% yield) of the titlecompound as a white solid. MS(ESI) 596.0(M⁺).

f)(R)-2-(3-{3-[(2-Chloro-3-(trifluoromethyl)-benzyl)-(2,2-diphenylethyl)-amino]-2-methyl-propoxy}phenyl)-1-morpholin-4-yl-ethanonehydrochloride salt

Following the procedure of Intermediate 1 step (e) except(R)-2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]-2-methyl-propoxy}-phenyl)aceticacid was used instead of2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl)(2,2-diphenylethyl)-amino]-propoxy}-phenylacetic acid in step 1(e) the title compound was prepared as a whitesolid.

MS(ESI) 665.4 (M⁺).

Intermediate 112-(3-{(R)-3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-butoxy}-phenyl)-1-morpholin-4-yl-ethanonehydrochloride salt

a) (S)-[3-(3-Hydroxy-butoxy)-phenyl]-acetic acid methyl ester

To a stirring solution of (3-hydroxy-phenyl)-acetic acid methyl ester(0.93 g, 0.0056 mole) and toluene-4-sulfonic acid-(S)-3-hydroxy-butylester (1.5 g, 0.0061 mole) in anhydrous DMF (10 mL) was added Cs₂CO₃(2.0 g, 0.006 mole). The reaction was heated to 100° C. and stirred for4 hours. The mixture was cooled to RT and filtered. The filtrate waspoured into H₂O (50 mL) and extracted three times with EtOAc. Thecombined organic layers were dried over sodium sulfate, filtered, andconcentrated. The crude product was subjected to column chromatographyover silica gel (silica gel 60, EM Science) using 30% EtOAc:hexane aseluent to afford 0.59 g (44% yield) of the title compound as an oil: MS(ESI) 239.0 (M+H⁺).

b) (S)-{3-[3-(Toluene-4-sulfonyloxy)-butoxy]-phenyl}-acetic acid methylester

To a stirring solution of (S)-[3-(3-hydroxy-butoxy)-phenyl]-acetic acidmethyl ester (589 mg, 2.47 mmol) and triethylamine (376 mg, 3.71 mmol)in dichloromethane (10 mL) at 0° C. was added p-toluenesulfonyl chloride(944 mg, 4.95 mmol). The reaction was then stirred at RT for 30 min. andrefluxed overnight. The reaction mixture was poured into H₂O (40 mL) andextracted three times with dichloromethane. The combined organicextracts were dried over sodium sulfate, filtered, and concentrated. Thecrude product was purified by column chromatography over silica gel(silica gel 60, EM Science) using 15% EtOAc:hexane as eluent to afford0.61 g (63% yield) of the title compound as an oil: MS (ESI) (M+H⁺).

c)(R)-2-(3-{3-[(2,2-Diphenylethyl)amino]-3-methyl-propoxy}-phenyl)aceticacid methyl ester

To a stirring solution of 2,2-diphenethylamine (151 mg, 0.765 mmol) and(S){3-[3-(toluene-4-sulfonyloxy)-butoxy]-phenyl)-acetic acid methylester (300 mg, 0.765 mmol) in 5 mL acetonitrile was treated with solidK₂CO₃ (317 mg, 2.30 mmol). The reaction was heated to reflux and stirredfor 48 hours. Upon cooling to room temperature, the reaction wasfiltered, washed with acetonitrile, and the filtrate was concentrated.The crude product was purified by column chromatography over silica gel(silica gel 60, EM Science) using 50% EtOAc:hexane as eluent to afford200 mg (63% yield) of the title compound as an oil: MS (ESI) 418.2(M+H⁺).

d)(R)-2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]-3-methyl-propoxy}-phenyl)aceticacid methyl ester

To a stirring solution of(R)-2-(3-{3-(2,2-diphenylethyl)amino]-3-methyl-propoxy}-phenyl)aceticacid methyl ester (150 mg, 0.359 mmol) and2-chloro-3-trifluoromethylbenzaldehyde (164 mg, 0.79 mmol) indichloromethane (5 ml) was added sodium triacetoxyborohydride (168 mg,0.79 mmol) and acetic acid (10 drops). The reaction mixture was stirredat RT for three days. Solvent was next removed, the residue wasdissolved in EtOAc, and then washed with saturated aqueous NaHCO₃. TheEtOAc layer was dried over Na₂SO₄, filtered, and concentrated. The crudemixture was purified by preparative HPLC (TMC CombiPrep PDS, 75×30 mm,25 mL/min, acetonitrile:H₂O, UV detection at 254 nm) to give 140 mg(64%) of the title compound as a viscous oil. MS(ESI) 610.0(M⁺).

e)(R)-2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]-3-methyl-propoxy}-phenyl)aceticacid hydrochloride salt

Following the procedure of Intermediate 8 step(e) except(R)-2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]-3-methyl-propoxy}-phenyl)aceticacid methyl ester was used instead of(R)-2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]-2-methyl-propoxy}-phenyl)aceticacid methyl ester in step 8(e), the title compound was isolated to givea white solid (100 mg, 89%). MS(ESI) 596.0 (M⁺).

f)2-(3-{(R)-3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-butoxy}-phenyl)-1-morpholin-4-yl-ethanonehydrochloride salt

Following the procedure of Intermediate 1 step (e) except(R)-2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)aminod-3-methyl-propoxy}-phenyl)aceticacid was used instead of2-(3-(3-[[2-chloro-3-(trifluoromethyl)benzyl)(2,2-diphenylethyl)-amino]-propoxy}-phenylacetic acid in step 1(e) the title compound was prepared as a whitesolid.

MS(ESI) 665.4 (M⁺).

EXAMPLE 139 (METHOD A)(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-(3-{3-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenoxy}-propyl)-aminehydrochloride salt

A solution of2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-1-(4-methyl-piperazin-1-yl)-ethanone(108 mg, 0.162 mmol) (Intermediate 2 above) and 15 ml anhydrous toluene(Aldrich) was cooled down to −40° C. in a dry ice-acetonitrile bath. Tothis solution was added 4 eq of DIBAL-H (0.45 ml of a 1.5M solution intoluene, Aldrich) in a dropwise fashion. The resulting mixture wasallowed to warm up to room temperature and stirred overnight. Thereaction was then quenched with water. The reaction mixture wasconcentrated in vacuo, and extracted with EtOAc (3×). The combinedorganic layers were washed with brine (1×), dried over sodium sulfate,filtered and concentrated in vacuo. The crude product was purified bycolumn chromatography over silica gel (silica gel 60, EM science) using5% MeOH:dichloromethane as eluent). The free base was dissolved indichloromethane, 1 eq. of HCl (1M in Et₂O, Aldrich) was added, and themixture was concentrated to afford the title compound as a solid (78 mg,70%). MS(ES) m/e 650.4 (M⁺).

EXAMPLE 140 (METHOD B)(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[3-(2-methylamino-ethyl)-phenoxy]-propyl}-aminehydrochloride salt

To a stirring solution of2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-N-methyl-acetamide(101 mg, 0.17 mmol) (Intermediate 3 above) in anhydrous THF (10 mL) wasadded BH₃ THF (0.34 ml, 1 M solution in THF). The resulting solution wasthen heated to reflux for 1.5 hours. Aqeous HCl (0.34 ml. 6 M) was thenadded to the reaction and the mixture was heated at reflux for 30 min.After cooling to RT, the reaction mixture was concentrated in vacuo andextracted with EtOAc (3×). The combined organic layers were washed withbrine (1×), dried over sodium sulfate, filtered and concentrated invacuo. The crude product was purified by column chromatography oversilica gel (silica gel 60, EM science) using 5% MeOH:dichloro-methane aseluent. The free base was dissolved in dichloromethane, 1 eq. of HCl (1Min Et₂O) was added, and the mixture was evaporated to afford the titlecompound as a white solid (52 mg, 50%). MS(ES) m/e 581.4 (M⁺).

EXAMPLE 141-149

Following the same procedure (method A or B) as in Example 139 or 140the following 9 amines were prepared from the corresponding amides:

Ex. # & method Amide Chemical Name MS 141 In. 4(2-Chloro-3-trifluoromethyl-benzyl)-(2,2- 647.4 Adiphenyl-ethyl)-[3-(3-{2-[(1H-imidazol-2- (M⁺) ylmethyl)-amino]-ethyl}-phenoxy)- propyl]-amine hydrochloride salt 142 In. 7(2-Chloro-3-trifluoromethyl-benzyl)-(2,2- 595.4 Adiphenyl-ethyl)-{3-[3-(2-ethylamino- (M⁺) ethyl)-phenoxy]-propyl}-aminehydrochloride salt 143 In. 5 [3-(3-{2-[(5-Bromo-thiophen-2-ylmethyl)-741.2 A amino]-ethyl}-phenoxy)-propyl]-(2- [M − H]⁺chloro-3-trifluoromethyl-benzyl)-(2,2- diphenyl-ethyl)-aminehydrochloride salt 144 In. 6 (2-Chloro-3-trifluoromethyl-benzyl)-(2,2-663.4 A diphenyl-ethyl)-[3-(3-{2-[(thiophen-2- (M⁺)ylmethyl)-amino]-ethyl}-phenoxy)- propyl]-amine hydrochloride salt 145In. 8 (2-Chloro-3-trifluoromethyl-benzyl)-{3-[3- 595.2 B(2-dimethylamino-ethyl)-phenoxy]- (M⁺)propyl}-(2,2-diphenyl-ethyl)-amine hydrochloride salt 146 In. 9(2-Chloro-3-trifluoromethyl-benzyl)-(2,2- 621.4 Bdiphenyl-ethyl)-{3-[3-(2-pyrrolidin-1-yl- (M⁺)ethyl)-phenoxy]-propyl}-amine hydrochloride salt 147 In. 1(2-Chloro-3-trifluoromethyl-benzyl)-(2,2- 637.6 Bdiphenyl-ethyl)-{3-[3-(2-morpholin-4-yl- (M⁺)ethyl)-phenoxy]-propyl}-amine hydrochloride salt 148 In. 11(2-Chloro-3-trifluoromethyl-benzyl)-(2,2- 653.1 Adiphenyl-ethyl)-{(R)-1-methyl-3-[3-(2- (M⁺)morpholin-4-yl-ethyl)-phenoxy]-propyl}- amine hydrochloride salt 149 In.10 (2-Chloro-3-trifluoromethyl-benzyl)-(2,2- 653.4 Adiphenyl-ethyl)-{(R)-2-methyl-3-[3-(2- (M⁺)morpholin-4-yl-ethyl)-phenoxy]-propyl}- amine hydrochloride salt

EXAMPLE 150{3-[3-(2-Amino-ethyl)-phenoxy]-propyl}-(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-aminehydrochloride salt

a)2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-acetamide

Following the procedure of Intermediate 1 (a)-(e) except ammonia (1M inmethanol) was substituted for morpholine in step 1(e), the titlecompound was obtained as an oil (84.6 mg, 90%). MS(ES) m/e 581.4 (M⁺).

b){3-[3-(2-Amino-ethyl)-phenoxy]-propyl}-(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-aminehydrochloride salt

Following the procedure of Example 140 except2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-acetamidewas used instead of2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-N-methyl-acetamide,the title compound was obtained as a solid (40 mg, 45%). MS(ES) m/e567.2 (M⁺).

EXAMPLE 151[2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-ethyl]-isopropyl-aminehydrochloride salt

Following the procedure of Example 150 step (a)-(b) exceptisopropylamine was substituted for ammonia in step (a), the titlecompound was obtained as a solid (50 mg, 48% for two steps). MS(ES) m/e609.2 (M⁺).

EXAMPLE 152[2-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-ethyl]-propyl-aminehydrochloride salt

Following the procedure of Example 150 (a)-(b) except n-propylamine wassubstituted for ammonia in step (a), the title compound was obtained asa solid (45 mg, 43% for two steps). MS(ES) m/e 609.2 (M⁺).

EXAMPLE 1532-[2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-ethylamino]-ethanolhydrochloride salt

Following the procedure of Example 150 (a)-(b) except amino-acetic acidtert-butyl ester for ammonia in step (a), the title compound wasobtained as a solid (44.7 mg, 42.7% for two steps). MS(ES) m/e 611.4(M⁺).

EXAMPLE 154(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-{2-[(1-methyl-1H-imidazol-2-ylmethyl)-amino]-ethyl}-phenoxy)-propyl]-aminehydrochloride salt

Following the procedure of Example 150 (a)-(b) except(1-Methyl-1H-imidazol-2-yl)-methylamine was substituted for ammonia instep (a), the title compound was obtained as a solid (84 mg, 74% for twosteps). MS(ES) m/e 661.0 (M⁺).

EXAMPLE 155(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[3-(2-thiomorpholin-4-yl-ethyl)-phenoxy]-propyl}-aminehydrochloride salt

a)2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-1-thiomorpholin-4-yl-ethanone

Following the procedure of Intermediate 1 (a)-(e) except thiomorpholinewas substituted for morpholine in step 1(e), the title compound wasobtained as an oil (107 mg, 99%). MS(ES) m/e 667.4 (M⁺).

b){3-[3-(2-Amino-ethyl)-phenoxy]-propyl}-(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-aminehydrochloride salt

Following the procedure of Example 139 except2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-1-thiomorpholin-4-yl-ethanonewas used instead of2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-1-(4-methyl-piperazin-1-yl)-ethanone,the title compound was obtained as a solid (73 mg, 65%). MS(ES) m/e653.4 (M⁺).

EXAMPLE 156[2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-ethylamino]-aceticacid hydrochloride salt

a)(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-acetaldehyde

A solution of(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-aceticacid methyl ester (350 mg, 1.68 mmole) in anhydrous toluene (20 ml) wascooled down to −40° C. in a dry ice/acetonitrile bath. DIBAL-H (1.25 ml,1.5M solution in toluene, Aldrich) was added in a dropwise fashion. Theresulting mixture was stirred at −40° C. for 3 hours and then quenchedwith 0.01N HCl (aq.). The crude material was concentrated in vacuo andthen extracted with EtOAc (3×). The combined organic layers were washedwith brine (1×), dried over sodium sulfate, filtered and concentrated invacuo. Preparative HPLC (YMC, 75×30 mm, 25 ml/min, 70-100% CH₃CN)afforded the title compound as an oil, 0.15 g (45%). MS(ES) m/e 566.2(M⁺).

b)[2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-ethylamino]-aceticacid methyl ester

To a solution of(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-acetaldehyde(76 mg, 0.13 mmol) and glycine methyl ester (34 mg, 0.27 mmol) in1,2-dichloroethane (15 ml) was stirred as room temperature for 10minutes, and sodium triacetoxyborohydride (57 mg, 0.27 mmol) was added.Next two drops of glacial acetic acid was added. The reaction mixturewas stirred at room temperature for 18 hour and then quenched with 0.01Naqueous HCl (15 ml) The biphasic mixture was separated and the aqueouslayer was extracted with dichloromethane (3×). The organic layers werecombined with the 1,2-dichloroethane solution and were washed with brine(1×), dried over sodium sulphate, filtered and concentrated in vacuo.Preparative HPLC (YMC 75×30 mm, 25 ml/min, 90-100% CH₃CN) afforded titlecompound as an oil, 70 mg (81%).

c)[2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-ethylamino]-aceticacid hydrochloride salt

To a stirring solution of[2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-ethylamino]-aceticacid methyl ester (70 mg, 0.11 mmol) in THF (10 ml) and water (3.3 ml)was added lithium hydroxide monohydrate (12 mg, 0.28 mmol). Theresulting mixture was stirred at room temperature for 18 hours andacidified with HCl (0.5 ml, 1 M in water). The crude mixture wasconcentrated in vacuo and then extracted with EtOAc (3×). The combinedorganic layers were washed with brine (1×), dried over sodium sulfate,filtered and concentrated in vacuo. Preparative HPLC (YMC 75×30 mm, 25ml/min, 25-100% CH₃CN) afforded the title compound as the free base. Thediamine was treated with 1 M HCl in Et₂O (0.11 ml, 0.11 mmol), and theEt₂O was evaporated to afford the title compound as an off-white solid,31 mg (45%). MS(ES) m/e 625.4 (M⁺).

EXAMPLE 157[2-(3-{(R)-3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-butoxy}-phenyl)-ethylamino]-aceticacid hydrochloride salt

Following the procedure of Example 156 steps (a)-(c) except(R)-2-(3-{3-[[2-Chloro-3-(trifuoromethyl)benzyl](2,2-diphenylethyl)amino]-3-methyl-propoxy}-phenyl)aceticacid methyl ester was used in step (a) instead of(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-aceticacid methyl ester, the title compound was obtained as a solid. MS(ES)m/e 639.2 (M⁺)

EXAMPLE 158-160

The following compound were prepared in analogous fashion to Example 157steps (a)-(c) by substituting for glycine methyl ester in step (b):

Ex Amino Esters Chemical Names M/S 158 N-{[2-(3-{3-[(2-chloro-3-trifluoromethyl- 639.4 Methylamino-benzyl)-diphenylethyl-amino]- (M⁺) acetic acidpropoxy}-phenyl)-ethyl]-methyl- methyl ester amino}-acetic acidhydrochloride salt 159 2-Amino-2-2-[2-(3-{3-[(2-chloro-3-trifluoromethyl- 653.4 methyl-benzyl)-diphenylethyl-amino]- (M⁺) propionic acidpropoxy}-phenyl)-ethylamino]-2- methyl ester methyl-propionic acidhydrochloride salt 160 (S)-2-Amino-(S)-2-[2-(3-{3-[(2-chloro-3-trifluoro- 639.4 propionic acidmethyl-benzyl)-diphenylethyl-amino]- (M⁺) methyl esterpropoxy}-phenyl)-ethylamino]- propionic acid hydrochloride salt

EXAMPLES 161-162

The following compound were prepared in analogous fashion to Example 157steps (a)-(b) except (R)-pyrrolidine-2-carboxylic acid and(S)-pyrrolidine-2-carboxylic acid were substituted for glycine methylester in step (b):

Ex Amino Acid Chemical Name MS 161 (R)-(R)-1-[2-(3-{3-[(2-chloro-3-trifluoromethyl- 665.4 Pyrrolidine-benzyl)-diphenylethyl-amino]-propoxy}- (M⁺) 2-phenyl)-ethyl]-pyrrolidine-2-carboxylic acid carboxylic hydrochloridesalt acid 162 (S)- (S)-1-[2-(3-{3-[(2-chloro-3-trifluoromethyl- 665.4Pyrrolidine- benzyl)-diphenylethyl-amino]-propoxy}- (M⁺) 2-phenyl)-ethyl]-pyrrolidine-2-carboxylic acid carboxylic hydrochloridesalt acid

EXAMPLE 163[2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-ethyl]-pyrimidin-2-yl-aminehydrochloride salt

To a stirring solution of{3-[3-(2-amino-ethyl)-phenoxy]-propyl}-(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amine(57 mg, 0.1 mml, Example 150) and 2-Chloro-pyrimidine (97 mg, 0.85 mmol)in ethanol (10 mL) was added triethylamine (0.5 ml, 3.75 mmol). Theresulting solution was refluxed for 72 hours and then concentrated invacuo. Purification by preparative HPLC (YMC 75×30 mm, 25 m/min, 95-100%CH₃CN) afforded the desired pyrimidine product. The free base wastreated with 1 M HCl in Et₂O (0.1 ml) and the mixture was concentratedin vacuo to afford the title compound as a solid, 44 mg (64%). MS(ES)m/e 645.4 (M⁺).

EXAMPLE 1642-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-morpholin-4-yl-phenoxy)-propyl]-aminehydrochloride salt

a) (2,2-Diphenylethyl)(2-chloro-3-trifluoromethyl-benzyl)amine

To a stirring solution of 2,2-diphenethylamine (2.0 g, 0.010 mole) and2-chloro-3-trifluoromethylbenzaldehyde (2.33 g, 0.011 mole) indichloromethane (20 mL) was added sodium triacetoxyborohydride (2.36 g,0.011 mole) and acetic acid (2.0 mL). The reaction mixture was stirredovernight. The solvent was removed and the residue was dissolved inethyl acetate. The ethyl acetate solution was washed with saturatedNaHCO₃, the ethyl acetate extracts were dried over Na₂SO₄, filtered, andconcentrated. The crude product was subjected to column chromatographyover silica gel (silica gel 60, EM Science) using 30% ethylacetate:hexane as eluent to afford 3.0 g (76% yield) of the titlecompound as a yellow oil: MS (ESI) 390.0 (M+H⁺).

b)N-(2,2-Diphenylethyl)-N-(3-hydroxy-propyl)-N-(2-chloro-3-trifluoromethyl-benzyl)amine

To a stirring solution of 3-bromo-propanol (77 ul, 0.84 mmol) inacetonitrile (10 ml) was added Nal (0.25 g, 1.7 mmol) and K₂CO₃ (0.23 g,1.7 mmol). The mixture was stirred at 85° C. for 1 h, and thenN-(2,2-diphenylethyl)-N-(2-chloro-3-trifluoromethyl-benzyl)amine (0.43g, 1.12 mmol) was added. The reaction mixture was heated at 85° C.overnight. Solvent was removed, the residue was washed with H₂O, andextracted twice with EtOAc. The EtOAc extracts were dried over Na₂SO₄,filtered, and concentrated. The crude mixture was purified bypreparative HPLC (TMC CombiPrep PDS, 75×30 mm, 25 mL/min,acetonitrile:H₂O, UV detection at 254 nm) to give 225 mg (60%) of thetitle compound as a white solid. MS (ESI) 448.0 (M+H⁺).

c)(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-morpholin-4-yl-phenoxy)-propyl]-aminehydrochloride salt

A stirring solution of3-[(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propan-1-ol(282 mg, 0.38 mmol) in toluene (25 mL) was treated with3-morpholin-4-yl-phenol (75 mg, 0.42 mmol). Polymer boundtriphenylphosphine (224 mg, 0.67 mmol, 3 mmol/g, Fluka Chemie) was thenadded, and the mixture was stirred for 15 minutes. The reaction mixturewas then cooled to 0° C. and diisopropylazodicarboxylate (127 mg, 0.63mmol) was added in a dropwise fashion. After stirring at roomtemperature overnight, the crude reaction mixture was filtered and thesolid washed with toluene (25 mL). The filtrate was concentrated invacuo. Purification by preparative HPLC (YMC 75×30 mm, 25 ml/min,85-100% CH₃CN over) led to the isolation of the morpholine product. Thefree base was treated with 1 M HCl in Et₂O (0.1 ml) and the mixture wasconcentrated in vacuo to afford the title compound as a solid, 104 mg(41%). MS(ES) m/e 609.4 (M⁺).

EXAMPLE 165-167

Following the same procedure of Example 164 (a)-(c), except substitutingthe below-named starting alcohol for 3-morpholin-4-yl-phenol in step(c), the following compounds were prepared:

Ex. starting alcohol chemical name M/S 165 3-Piperidin-1-yl-(2-Chloro-3-trifluoromethyl-benzyl)- 607.4 phenol(2,2-diphenyl-ethyl)-[3-(3-piperidin- (M⁺) 1-yl-phenoxy)-propyl]-aminehydrochloride salt 166 3-Diethylamino-(3-{3-[(2-chloro-3-trifluoromethyl- 595.4 phenolbenzyl)-diphenylethyl-amino]- (M⁺) propoxy}-phenyl)-diethyl-aminehydrochloride salt 167 3-(2,5-Dimethyl-(2-Chloro-3-trifluoromethyl-benzyl)- 617.2 pyrrol-1-yl)-{3-[3-(2,5-dimethyl-pyrrol-1-yl)- (M⁺) phenolphenoxy]-propyl}-(2,2-diphenyl- ethyl)-amine

EXAMPLE 168(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-piperazin-1-yl-phenoxy)-propyl]-aminehydrochloride salt

a) 4-(3-Hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester

To a stirring solution of 3-piperazin-1-yl-phenol (1.50 g, 8.43 mmol) in1,4-dioxane (25 mL) was added di-t-butyl dicarbonate (2.02 g, 9.26mmol). The resulting mixture was stirred at room temperature for 36hours and then concentrated in vacuo. The crude product was dissolved inEtOAc and washed with saturated aqueous sodium bicarbonate solution (1×)and brine (1×). The EtOAc layer was dried over sodium sulfate, filteredand concentrated in vacuo to afford the title compound as a light yellowsolid, 2.05 g (86%). MS(ES) m/e 279.4 (M+H⁺).

b)4-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-piperazine-1-carboxylicacid tert-butyl ester

To a stirring solution of3-[(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propan-1-ol(448 mg, 1.0 mmol) in toluene (30 mL) was added4-(3-hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (419mg, 1.50 mmol). Polymer bound triphenylphosphine (500 mg, 1.50 mmol, 3mmol/g, Fluka Chemie) was then added, and the mixture stirred for 15minutes. The reaction mixture was then cooled to 0° C. anddiisopropylazodicarboxylate (303 mg, 1.50 mmol) was added in a dropwisefashion. After stirring at room temperature overnight, the crudereaction mixture was filtered and the solid washed with toluene.Concentration of the filtrate in vacuo followed by purification by flashsilica gel chromatography (silica gel 60, EM science; 15% EtOAc:hexane)afforded title compound as an oil (0.59 g, 84%). MS(ES) m/e 708.4 (M⁺).

c)(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-piperazin-1-yl-phenoxy)-propyl]-aminehydrochloride salt

A solution of4-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-piperazine-1-carboxylicacid tert-butyl ester (475 mg, 0.67 mmol) in a 1:1 mixture of 3M HCl(aq.) and methanol (30 mL total) was stirred at room temperature for 18hours. The mixture was concentrated in vacuo, and the crude material wasdissolved in EtOAc. The EtOAc solution was washed with saturated aqueoussodium bicarbonate solution (3×) and brine (1×), dried over sodiumsulfate, and filtered. The EtOAc extracts were concentrated and thecrude piperazine was treated with 1 M HCl (Et₂O) to afford the titlecompound as a solid, 415 mg (100%). MS(ES) m/e 608.4 (M⁺).

EXAMPLE 169(2-Chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-[3-(3-piperazin-1-yl-phenoxy)-propyl]-aminehydrochloride salt

a)3-[(2-chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-amino]-propan-1-ol

Following the procedure of Example 164 step(b) except(S)-(2-Chloro-3-trifluoromethyl-benzyl)-(2-phenyl-propyl)-amine (Example10(a) was used in step (b) instead of 2,2-diphenylethylamine the titlecompound was prepared as a clear oil (30%). MS (ESI) 385.8 (M⁺).

b)(2-Chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-[3-(3-piperazin-1-yl-phenoxy)-propyl]-aminehydrochloride salt

Following the procedure for Example 168 steps (a)-(c) except3-[(2-chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-amino]-propan-1-olwas used in step (b) instead of3-[(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propan-1-olthe title compound was synthesized as a white solid, 199 mg (68%). MS(ESI) 546.0 (M⁺).

EXAMPLE 170(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[(R)-2-methyl-3-(3-piperazin-1-yl-phenoxy)-propyl]-aminehydrochloride

a)N-(2,2-Diphenylethyl)-N-((R)-2-Methyl-3-hydroxy-propyl)-N-(2-chloro-3-trifluoromethyl-benzyl)amine

Following the procedure of Example 164 steps (a)-(b) except(S)-3-bromo-2-methyl-propanol was used in step (b) instead of3-bromo-propanol the title compound was prepared as a yellow oil (25%).MS (ESI) 461.9 (M⁺).

b)(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[(R)-2-methyl-3-(3-piperazin-1-yl-phenoxy)-propyl]-aminehydrochloride

Following the procedure for Example 168 steps (a)-(c) exceptN-(2,2-diphenylethyl)-N-((R)-2-methyl-3-hydroxy-propyl)-N-(2-chloro-3-trifluoromethyl-benzyl)aminewas used in step (b) instead of3-[(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propan-1-olthe title compound was synthesized as a white solid, 153 mg (57%). MS(ESI) 622.4 (M⁺).

EXAMPLE 171(2-Chloro-3-trifluoromethyl-benzyl)-isobutyl-[3-(3-piperazin-1-yl-phenoxy)-propyl]-aminehydrochloride salt

a) 3-[(2-chloro-3-trifluoromethyl-benzyl)-isobutyl-amino]-propan-1-ol

Following the procedure of Example 164 steps (a)-(b) excepti-butyl-amine was used in step (a) instead of 2,2-diphenethylamine thetitle compound was prepared as a clear oil (25%). MS (ESI) 324.2 (M+H⁺).

b)(2-Chloro-3-trifluoromethyl-benzyl)-isobutyl-[3-(3-piperazin-1-yl-phenoxy)-propyl]-aminehydrochloride salt

Following the procedure for Example 168 steps (a)-(c) except3-[(2-chloro-3-trifluoromethyl-benzyl)-isobutyl-amino]-propan-1-ol wasused in step (b) instead of3-[(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propan-1-olthe title compound was synthesized as a white solid, 192 mg (60%). MS(ESI) 484.2 (M⁺).

EXAMPLE 172[4-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-piperazin-1-yl]-aceticacid hydrochloride salt

a)[4-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-piperazin-1-yl]-aceticacid methyl ester

To a solution of(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-piperazin-1-yl-phenoxy)-propyl]-aminehydrochloride (114 mg, 0.187 mmol—Example 168) in methanol (15 mL) wastreated with bromo-acetic acid methyl ester (57 mg, 0.375 mmol) anddiisopropyl-ethyl-amine (48 mg, 0.375 mmol). The resulting solution washeated at 50° C. for 3 hours, cooled to room temperature, andconcentrated. The crude material was dissolved in EtOAc and washed withwater (1×). The organic layer was then washed with brine (1×), driedover sodium sulfate, and filtered. The EtOAc was concentrated and thesample was dried under vacuum to title compound as an oil (99 mg, 78%).MS(ES) m/e 622.2 ([M−COOCH₃]⁺).

b)[4-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-piperazin-1-yl]-aceticacid hydrochloride salt

To a stirring solution of[4-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-piperazin-1-yl]-aceticacid methyl ester (99 mg, 0.146 mmol) in a mixture of THF and water(3:1; 12 ml) was added lithium hydroxide monohydrate (8 mg, 0.192 mmol).The resulting mixture was stirred at room temperature for 18 hours andthen acidified with 1 M aqueous HCl (0.2 ml). The mixture wasconcentrated in vacuo, water (5 mL) was added, and the crude materialwas extracted with EtOAc (3×). The combined organic layers were washedwith brine (1×), dried over sodium sulfate, and filtered. The organiclayer was concentrated, and the crude amine was treated with 1 M HCl(Et₂O). The resulting precipitate was dried under vacuum to afford thetitle compound as a solid (87 mg, 97%). MS(ES) m/e 666.0 (M⁺).

Following the procedure of Example 172 (a)-(b) except NH-piperazinesfrom Examples 173, 174, and 175 were used in step 172(a) instead of(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-piperazin-1-yl-phenoxy)-propyl]-amine,the following compounds were prepared:

Free base Ex. of Chemical Name MS 173 Example[4-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)- 604.0 169((S)-2-phenyl-propyl)-amino]-propoxy}- (M⁺)phenyl)-piperazin-1-yl]-acetic acid hydrochloride salt 174 Example[4-(3-{(R)-[(2-chloro-3-trifluoromethyl- 680.2 170benzyl)-diphenylethyl-amino]-methyl- (M⁺)propoxy}-phenyl)-piperazin-1-yl]-acetic acid hydrochloride salt 175Example [4-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)- 542.2 171isobutyl-amino]-propoxy}-phenyl)-piperazin-1- (M⁺) yl]-acetic acidhydrochloride salt

EXAMPLE 176(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[3-(4-methyl-piperazin-1-yl)-phenoxy]-propyl}-aminemethanesulfonate

To a stirring solution of(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-piperazin-1-yl-phenoxy)-propyl]-amine(150 mg, 2.46 mmol) in anhydrous DMF (20 ml) was added iodomethane (16.8uL, 2.71 mmol) and diisopropylethylamine (86 uL, 4.93 mmol). Theresulting solution was heated at 50° C. for 4 hours and thenconcentrated. Purification by flash silica gel chromatography (silicagel 60, EM science; 3% MeOH and 0.5% NH₂OH in CH₂Cl₂) afforded theN-methylated product. The amine was dissolved in CH₂Cl₂ andmethansulfonic acid (2 equivalents) was added. The methylene chloridesolution was concentrated and the resulting bis-methanesulfonate saltwas dried under vacuum to yield the title compound as a solid, 56 mg(37%). MS(ES) m/e 622.4 (M⁺).

EXAMPLE 177(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-pyrrolidin-1-yl-phenoxy)-propyl]-aminehydrochloride salt

a) 1-(3-Methoxy-phenyl)-pyrrolidine

To a stirring solution of 3-methoxy-phenylamine (571 mg, 4.6 mmol) inanhydrous toluene (40 ml) was added 1,4-dibromo-butane (1.0 g, 4.6 mmol)and diisopropylethylamine (0.59 g, 4.6 mmol). The resulting solution washeated to reflux for 24 hours and then concentrated in vacuo. The crudematerial was purified by column chromatography over silica gel (silicagel 60, EM science, 5% EtOAc:hexanes) and the title compound wasobtained as an oil (754 mg, 92%). MS(ES) m/e 178.4 ([M+H]⁺).

b) 3-Pyrrolidin-1-yl-phenol

To a stirring solution of 1-(3-methoxy-phenyl)-pyrrolidine (354 mg, 2mmol) in dichloromethane (30 ml) at 0° C. was added BBr₃ (4.0 ml, 4mmol, 1 M solution in dichloromethane) in a dropwise fashion. Theresulting solution was stirred over night at room temperature and thenpoured into ice water (30 ml). The aqueous mixture was extracted withdichloromethane (3×). The combine organic layers were washed with brine(1×), dried over sodium sulfate, and filtered. The dichloromethanefiltrate was concentrated to afford the title compound as an oil (317mg, 97%). MS(ES) m/e 164.2 ([M+H]⁺).

c)(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-pyrrolidin-1-yl-phenoxy)-propyl]-aminehydrochloride salt

Following the procedure of Example 164 (a)-(c) except3-pyrrolidin-1-yl-phenol was used instead of 3-morpholin-4-yl-phenol instep (c) the title compound was obtained as a solid. MS(ES) m/e 593.2(M⁺).

EXAMPLE 178(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenylamino)-aceticacid hydrochloride salt

a)[tert-Butoxycarbonyl-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-amino]-aceticacid methyl ester

To a solution of sodium hydride (18.8 mg, 0.47 mmol, 60% in mineral oil)in anhydrous DMF (10 mL) at 0° C. and DMSO (10 ml) was added dropwise asolution of(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-carbamicacid tert-butyl ester (150 mg, 0.235 mmol) in DMF (5 ml). The solutionwas stirred at 0° C. for 20 minutes and was then treated withbromo-acetic acid methyl ester (72 mg 0.47 mmol). The resulting solutionwas warmed to room temperature and stirred for 6 hours. The reactionmixture was poured into ice water (30 ml). The mixture was extractedwith EtOAC (3×) and the combine organic layers were washed withsaturated aqueous sodium bicarbonate (2×), brine (×), dried over sodiumsulphate, and filtered. The ethyl acetate filtrate was concentrated toafford the title compound as an oil. MS(ES) m/e 711.2 (M⁺).

b)(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenylamino)-aceticacid methyl ester

To a solution of[tert-butoxycarbonyl-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy)phenyl)-amino]-aceticacid methyl in 4 M aqueous HCl (7.5 ml) and methanol (7.5 ml) wasstirred at room temperature for 18 hours and was then concentrated invacuo. The resulting mixture was dissolved in EtOAc and the combineorganic layers were washed with saturated aqueous sodium bicarbonatesolution (2×), brine (1×), dried over sodium sulfate, and filtered. Theethyl acetate filtrate was concentrated to afford the title compound asan oil. MS(ES) m/e 611.2 (M⁺).

c)(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenylamino)-aceticacid Hydrochloride

To a stirring solution of(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenylamino)-aceticacid methyl ester in THF (6 ml) and water (2 ml) was added lithiumhydroxide monohydrate (20 mg, 0.47 mmol) and the mixture was stirred atroom temperature for 6 hours. The reaction mixture was acidified with 1M aqueous HCl (0.5 mL). The aqueous mixture was concentrated in vacuoand the crude material was dissolved in EtOAc. The ethyl acetatesolution was washed with brine (1×), dried over sodium sulfate, andfiltered. The organic layer was concentrated, and the crude amine wastreated with 1 M HCl (Et₂O). The resulting precipitate was dried undervacuum to afford the title compound as a solid. MS(ES) m/e 597.4 (M⁺).

EXAMPLE 179[(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-N-methyl-amino]-aceticacid hydrochloride salt

a)[(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-N-methyl-amino]-aceticacid methyl ester

A solution of(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-N-methyl-amine(81 mg, 0.15 mmol) in methanol (15 ml) was treated with bromo-aceticacid methyl ester (46 mg, 0.30 mmol) diisopropylethylamine (46 mg, 0.36mmol). The resulting solution was heated at 50° C. for 4 hours, cooleddown and concentrated. The crude material was dissolved in EtOAc andwashed with brine (1×), dried over sodium sulfate, and filtered. Thefiltrate was concentrated to afford title compound as an oil (70 mg,76%). MS(ES) m/e 625.2 (M⁺).

b)[(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-N-methyl-amino]-aceticacid hydrochloride salt

Following the procedure of Example 178 step (c) except[(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-N-methyl-amino]-aceticacid methyl ester was used in step (c) instead of(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}phenylamino)-aceticacid methyl ester the title compound was obtained as a solid, 65 mg(96%). MS (ES) m/e 611.2 (M⁺).

EXAMPLE 180N-(2,2-Diphenylethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-[3-(2-methyl-2-aminopropyl)phenoxy]propylamine,dihydrochloride

a. 2,2-Dimethyl-3-(3-benzyloxyphenyl)propionic acid

A solution of diisopropylamine (1.55 mL, 11.9 mmole) in 20 mL of THF wascooled to −78° and treated with n-BuLi (6.5 mL 1.6N solution in hexane,10.4 mmole). After 10 minutes, a solution of isobutyric acid (436 mg,4.96 mmole) in 3 mL of THF was added, followed by HMPA (1.74 mL, 10mmole). The reaction was allowed to warm to 23°, then heated at 55° for30 minutes. The reaction was cooled to −78° and a solution of3-benzyloxybenzyl chloride (1.15 g, 4.96 mmole) in 6 mL of THF wasadded. The reaction was warmed to 23° for 30 minutes, then heated at 55°for 30 minutes. The reaction was cooled, diluted with H₂O, acidifiedwith 3N HCl, and extracted with Et₂O. The extracts were washed threetimes with H₂O, dried and the solvent removed, and gave the titledcompound as a white powder, 1.2 g (85% yield). MS (ESI) 285 (MH⁺).

b. Methyl 2,2-dimethyl-3-(3-benzyloxyphenyl)propionate

A solution of 2,2-dimethyl-3-(3-benzyloxyphenyl)propionic acid (400 mg,1.4 mmole) in 20 mL of MeOH and 0.5 mL conc. H₂SO₄ was refluxed for 18hours. The reaction was cooled, diluted with H₂O and extracted withEt₂O. The extracts were washed with H₂O, three times with aqueousNaHCO₃, dried, and the solvent evaporated. The residue waschromatographed over a silica gel column, and elution with a mixture ofCH₂Cl₂, hexane and MeOH (50:50:1) gave the titled compound, 208 mg (50%yield). MS (ESI) 299 (MH⁺).

c. Methyl 2,2-dimethyl-3-(3-hydroxyphenyl)propionate

A solution of methyl 2,2-dimethyl-3-(3-benzyloxyphenyl)propionate (208mg, 0.7 mmole) in 10 mL of MeOH and 1 mL of 1N HCl was treated with 10%Pd/C (100 mg) and hydrogenated on a Parr shaker with 50 psi H₂ pressurefor 1 hour. The catalyst was filtered, and the filtrate wasconcentrated, diluted with H₂O and extracted with Et₂O. The extractswere washed with H₂O, dried and the solvent removed, and gave the titledproduct, 140 mg (97% yield). MS (ESI) 209 (MH⁺).

d. MethylN-(2,2-diphenylethyl)-N-(2-chloro-3-trufluoromethylbenzyl)-2,2-dimethyl-3-(3-aminopropoxy)phenylpropionate

A solution of methyl 2,2-dimethyl-3-(3-hydroxyphenyl)propionate (135 mg,0.65 mmole) andN-(2,2-Diphenylethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-hydroxypropylamine(290 mg, 0.65 mmole) in 8 mL of THF was treated with Ph₃P (170 mg, 0.65mmole) and diisopropylazodicarboxylate (135 mg, 0.65 mmole) and stirredfor 16 hours. The reaction was diluted with H₂O and extracted with Et₂O.The extracts were washed with H₂O, dried, and the solvent removed. Theresidue was chromatographed on a silica gel column, and elution with 30%EtOAc in hexane gave the titled compound, 200 mg (50%). MS (ESI) 639(MH⁺).

e.N-(2,2-Diphenylethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-2,2-dimethyl-3-(3-aminopropoxy)phenylpropionicacid

A solution of methylN-(2,2-diphenylethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-2,2-dimethyl-3-(3-aminopropoxy)phenylpropionate(195 mg, 0.3 mmole) in 10 mL of MeOH, 1 mL of H₂O and 2 mL 2.5N NaOH wasrefluxed for 5 hours. The reaction was cooled, diluted with H₂O andacidified with 3N HCl to pH 5.1. The mixture was extracted with EtOAc,the extracts were washed with H₂O, dried and evaporated, and gave thetitled compound, 172 mg (92% yield). MS (ESI) 625 (MH⁺).

f.N-(2,2-Diphenylethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-[3-(2-methyl-2-aminopropyl)phenoxy]propylamine,dihydrochloride

A solution ofN-(2,2-Diphenylethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-2,2-dimethyl-3-(3-aminopropoxy)phenylpropionicacid, hydrochloride (158 mg, 0.24 mmole) in 10 mL of Me₂CO was treatedwith Et₃N (56 mg, 0.55 mmole) and cooled in an ice bath. A solution ofisobutylchloroformate (37 mg, 0.27 mmole) in 2 ml of Me₂CO was addeddropwise to the cold solution, and the reaction was stirred at 0° for 30minutes. A solution of NaN₃ (40 mg, 0.6 mmole) in 2 mL of H₂O was addedto the cold solution, and stirring was continued for 30 minutes. Thereaction was diluted with H₂O, and extracted with Et₂O. The extractswere washed with H₂O, and dried. The ethereal solution of the acyl azidewas slowly added with stirring to 50 mL of refluxing toluene. After theaddition, the toluene solution is stirred at 105° for 30 minutes, andall the solvents are removed. The residue is dissolved in 5 mL ofdioxane, treated with 5 mL of 6N HCl and heated at 100° for 30 minutes.The reaction was cooled, diluted with H₂O, made basic with aqueous NaOHand extracted with Et₂O. The extracts were washed with H₂O, dried, andthe solvents removed. The residue was chromatographed on a silica gelcolumn and the product was eluted with 10% MeOH in EtOAc. Thechromatographed product was converted to the dihydrochloride salt inEt₂O and isopropanol with 4N HCl in dioxane, and gave the titledproduct, 78 mg (55% yield). MS (ESI) 596 (MH⁺).

EXAMPLE 181N-(2,2-Diphenylethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-[2-hydroxymethyl]phenoxy)propylaminehydrochloride

a.N-(2,2-Diphenylethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carbomethoxyphenoxy)propylamine

A solution ofN-(2,2-Diphenylethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-hydroxypropylamine(186 mg, 0.42 mmole) and methyl 3-hydroxybenzoate (63 mg, 0.42 mmole) in15 mL of THF was treated with Ph₃P (110 mg, 0.42 mmole) anddiisopropylazodicarboxylate (93 mg, 0.46 mmole). The reaction wasstirred for 18 hours, diluted with H₂O, and extracted with Et₂O. Theextracts were washed with H₂O, dried, and the solvent evaporated. Theresidue was chromatographed on a silica gel column, and elution with 10%EtOAc in hexane gave the titled product, 64 mg (26% yield). MS (ESI) 583(MH⁺).

b.N-(2,2-Diphenylethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-[2-hydroxymethyl]phenoxy)propylamine

A solution ofN-(2,2-Diphenylethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carbomethoxyphenoxy)propylamine(52 mg, 0.09 mmole) in 5 mL of Et₂O at 0° was treated with LiAlH₄ (0.5mL of a 1N solution in THF). The reaction was stirred at 0° for 30minutes, 1 mL of EtOAc was added, and the reaction was allowed to warmto 23° for 30 minutes, diluted with H₂O and extracted with Et₂O. Theextracts were washed with H₂O, dried and the solvent removed. Theresidue was dissolved in Et₂O, the solution was treated with 4N HCl indioxane. The precipitated solid was filtered, washed with Et₂O anddried, and gave the titled compound, 27 mg (52%). MS (ESI) 555 (MH⁺).

EXAMPLE 182N-(2,2-Diphenylethyl)-N-2-chloro-3-trifluoromethylbenzyl)-3-(3-[2-hydroxy-2-methylpropyl]phenoxy)propylamine

A solution of MeMgl (5 mmole) in 10 mL of Et₂O was treated with asolution of methyl(3-{3-[[2-chloro-3-trifluoromethylbenzyl](2,2-diphenylethyl)amino]propoxy}-phenyl)acetate(120 mg, 0.2 mmole) in 2 mL of Et₂O. The reaction was heated, andconcentrated to 3 mL, and stirred at 23° for 30 minutes. The reactionwas diluted with cold, aqueous NH₄Cl and extracted with Et₂O. Theextracts were washed with H₂O, dried, and the solvent removed. Theresidue was chromatographed on a silica gel column, eluted with amixture of CH₂Cl₂, hexane and MeOH (50:50:1), and gave the titledproduct, 92 mg (77% yield). MS (ESI) 597 (MH⁺).

EXAMPLE 183N-(2,2-Diphenylethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-N-methylsulfonamidophenoxy)propylamine,hydrochloride

a. N-Methyl-3-nitrobenzene sulfonamide

A solution of MeNH₂ (10 mL of a 2N solution in THF) and 10 mL of H₂O wastreated with a solution of 3-nitrobenzene sulfonyl chloride (884 mg, 4mmole) in 4 mL of THF. The reaction was stirred for 2 hours, dilutedwith H₂O and extracted with Et₂O. The extracts were washed with H₂O,0.1N HCl, aqueous NaHCO₃, dried, and the solvent removed, and gave thetitled product, 608 mg (70%). MS (ESI) 217 (MH⁺).

b. N-Methyl-3-aminobenzene sulfonamide

A solution of N-methyl-3-nitrobenzene sulfonamide (608 mg, 2.8 mmole) in30 mL of MeOH and 5 mL of EtOAc was treated with 10% Pd/C (100 mg) andhydrogenated at 1 atmosphere H₂ pressure for 16 hours. The catalyst wasfiltered, and the filtrate evaporated. The residue was dissolved inEtOAc, washed with H₂O, dried and the solvent removed, and gave thetitled product, 498 mg (96%). MS (ESI) 187 (MH⁺).

c. N-Methyl-3-hydroxybenzene sulfonamide

N-Methyl-3-aminobenzene sulfonamide (488 mg, 2.62 mmole) was dissolvedin a mixture of 10 mL of H₂O and 2 mL of conc. H₂SO₄, and was cooled to−5°. A solution of NaNO₂ (207 mg, 3 mmole) in 2 mL of H₂O was addeddropwise at such a rate that the temperature doesn't exceed 0°. Thereaction was stirred for 10 minutes, urea (100 mg) was added, and thereaction was stirred an additional 10 minutes. The cold solution ofdiazo compound was slowly added with stirring to a 0° solution ofCu(NO₃)₂ dihydrate (10.3 g, 43 mmole) and Cu₂O (363 mg) in 100 mL ofH₂O. Stirring was continued for 30 minutes as the temperature wasallowed to warm to 23°. The heterogeneous reaction was extracted withEt₂O, and the extracts were extracted with 0.2N NaOH. The basic extractswere washed with Et₂O, acidified, and extracted with CH₂Cl₂. Theextracts were dried, and the solvent removed. The residue waschromatographed on a silica gel column, and elution with 50% EtOAc inhexane gave the titled product, 175 mg (36%). MS (ESI) 188 (MH⁺).

d. 3-Chloro-1-propanol tosylate

A solution of 3-chloro-1-propanol (1.88 g, 20 mmole) in 20 ml ofpyridine was treated at 0° with tosyl chloride (7.6 g, 40 mmole). Thesolution was warmed to 23°, and stirred 16 hours. The reaction wasdiluted with 100 mL of H₂O and stirred for 90 minutes, and extractedwith Et₂O. The extracts were washed with 1N HCl, dried, and the solventsthoroughly removed, and gave the titled product, 2.3 g (46%). MS (ESI)188 (MH⁺).

e. N-Methyl-3-(3-chloropropoxy)benzene sulfonamide

N-Methyl-3-hydroxybenzene sulfonamide (175 mg, 0.94 mmole) in 15 mL ofDMF was treated with Cs₂CO₃ (305 mg, 0.94 mmole), and stirred for 45minutes. A solution of 3-Chloro-1-propanol tosylate (223 mg, 0.90 mmole)in 3 mL of DMF was added. The reaction was heated at 55° for 3 hours,and stirred at 23° for 16 hours. The reaction was diluted with H₂O andextracted with Et₂O. The extracts were washed with H₂O, dried and thesolvent removed. The residue was chromatographed on a silica gel column,and elution with 30% EtOAc in hexane gave the titled product, 75 mg(30%). MS (ESI) 264 (MH⁺).

f. N-Methyl-3-(3-iodopropoxy)benzene sulfonamide

A solution of N-methyl-3-(3-chloropropoxy)benzene sulfonamide (75 mg,0.28 mmole) in 10 mL of Me₂CO was treated with Nal (200 mg) and themixture was refluxed for 32 hours. The reaction was diluted with H₂O,extracted with Et₂O. The extracts were washed with H₂O, aqueous NaHSO₃,dried, and the solvent removed, and gave the titled compound, 96 mg(95%). MS (ESI) 356 (MH⁺).

g.N-(2,2-Diphenylethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-N-methylsulfonamidophenoxy)propylamine,hydrochloride

A solution of N-methyl-3-(3-iodopropoxy)benzene sulfonamide (96 mg, 0.27mmole) and N-(2-chloro-3-trifluoromethylbenzyl)-2,2-diphenylethylamine(105 mg, 0.27 mmole) in 7 mL of MeCN was treated with excess NaHCO₃, andthe mixture refluxed for 18 hours. The solvents were evaporated, and theresidue taken up in EtOAc. The EtOAc was washed with aqueous NH₄Cl, H₂O,dried and the solvent removed. The residue was chromatographed on asilica gel column, and elution with 30% EtOAc in hexane afforded thetitled compound, 66 mg (40% yield). The hydrochloride salt was formed bytreating a solution of the titled compound in a mixture of Et₂O andisopropanol with 4N HCl in dioxane. MS (ESI) 618 (MH⁺).

EXAMPLE 184N-(2-[2-Chlorophenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,hydrochloride

a. 2-(2-Chlorophenyl)propionic acid

A solution of diisopropylamine (1.6 mL, 12 mmole) in 20 mL of THF at−78° was treated with n-BuLi (7.5 mL of a 1.6N solution in hexane, 12mmole). The solution was stirred 10 minutes, and then treated with HMPA(2.16 mL, 12 mmole), and stirred an additional 2 minutes. A solution ofo-chlorophenylacetic acid (850 mg, 5 mmole) in 4 mL of THF was added,the reaction was warmed to 23°, stirred 45 minutes, warmed to 50° andstirred for 5 minutes, and then cooled to 0°. Mel (1 mL) was added, thereaction was warmed to 23°, and stirred for 30 minutes. The reaction wasdiluted with H₂O, acidified with HCl, and extracted with Et₂O. Theextracts were washed with 0.1N HCl, H₂O, aqueous NaHSO₃, dried, and thesolvent removed, and gave the titled compounds as a white crystallinesolid, 603 mg (66% yield). MS (ESI) 185 (MH⁺).

b. N-(2-Chloro-3-trifluoromethylbenzyl)-2-(2-chlorophenyl)propionamide

A solution of 2-(2-chlorophenyl)propionic acid (350 mg, 1.9 mmole) and2-chloro-3-trifluoromethylbenzylamine (398 mg, 1.9 mmole) in 5 mL ofdichloroethane was treated with diisopropylcarbodiimide (0.3 mL, 1.9mmole) and the reaction was stirred for 16 hours. The solvent wasremoved, and the residue taken up in Et₂O. The Et₂O was washed with H₂O,0.1N HCl, and aqueous Na₂CO₃, dried and the solvent removed.Recrystallization from a mixture of CH₂Cl₂ and hexane gave the titledcompound, 265 mg (37% yield). MS (ESI) 376 (MH⁺).

c. N-(2-Chloro-3-trifluoromethylbenzyl)-2-(2-chlorophenyl)propylamine

A solution ofN-(2-chloro-3-trifluoromethylbenzyl)-2-(2-chlorophenyl)propionamide (265mg, 0.7 mmole) in 40 mL of toluene was treated with diisobutyl aluminumhydride (5 mL of a 1N solution in hexane), and the reaction was stirredfor 90 minutes. The reaction was diluted with 20 mL of Et₂O, aconcentrated aqueous solution of Rochelle salt was added, and themixture stirred for 60 minutes, at which time the emulsion had brokenapart. The organic layer was separated, washed with H₂O, aqueousRochelle salt, dried and the solvent removed, and gave the titledcompound, 221 mg (87%). MS (ESI) 362 (MH⁺).

d. Methyl 3-(3-chloropropyloxy)-phenyl acetate

A solution of methyl 3-hydroxyphenylacetate (2.55 g, 15.4 mmole) and3-chloro-1-propanol (1.45 g, 15.4 mmole) in 25 m[of THF was treated withPh₃P (4.04 g, 15.4 mmole) and diisopropylazodicarboxylate (3.42 g, 16.9mmole), and the mixture was stirred for 18 hours. The reaction wasdiluted with H₂O and extracted with Et₂O. The extracts were washed with0.1N NaOH, 0.1N HCl, and H₂O. The extracts were dried and the solventremoved. Chromatography on a silica gel column and elution with 10%EtOAc in hexane gave the titled compound, 1.94 g (52% yield). MS (ESI)243 (MH⁺).

e. Methyl 3-(3-iodopropyloxy)-phenyl acetate

A solution of methyl 3-(3-chloropropyloxy)-phenyl acetate (1.92 g, 7.9mmole) in 50 mL of Me₂CO was treated with NaI (3.6 g, 24 mmole), and themixture was refluxed for 24 hours. The reaction was diluted with H₂O andextracted with Et₂O. The extracts were washed with H₂O, aqueous NaHSO₃,dried, and the solvent removed, and gave the titled compound, 2.48 g(94% yield). MS (ESI) 335 (MH⁺).

f.N-(2-[2-Chlorophenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carbomethoxymethylenephenoxy)propylamine

A solution ofN-(2-chloro-3-trifluoromethylbenzyl)-2-(2-chlorophenyl)propylamine (220mg, 0.6 mmole) and methyl 3-(3-iodopropyloxy)-phenyl acetate (163 mg,0.48 mmole) in 15 mL of MeCN was treated with K₂CO₃ (165 mg, 1.2 mmole),and the mixture was refluxed for 16 hours. The solvent was removed, andthe residue was taken up in Et₂O. The Et₂O was washed with H₂O, aqueousNaHSO₃, dried and the solvent removed. The residue was chromatographedon a silica gel column, and elution with 30% EtOAc in hexane gave thetitled compound, 90 mg (33% yield). MS (ESI) 568 (MH⁺).

g.N-(2-[2-Chlorophenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,hydrochloride

A solution ofN-(2-[2-Chlorophenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carbomethoxymethylenephenoxy)propylamine(80 mg, 0.14 mmole) in 5 mL of MeOH was treated with 1 mL of H₂O and 0.5mL of 2.5N NaOH, and heated to 500 for 30 minutes. The reaction wasdiluted with H₂O, and acidified to pH 4, and extracted with EtOAc. Theextracts were washed with H₂O, dried, and the solvent removed. Theresidue was dissolved in Et₂O, a small amount of isopropanol was added,and treated with 4N HCl in dioxane. The precipitated solid was filtered,washed with Et₂O and dried, and gave the titled compound, 65 mg (81%).MS (ESI) 554 (MH⁺).

EXAMPLE 185N-(2-[3-Chlorophenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,hydrochloride

a. 2-(3-Chlorophenyl)propionic acid

The titled compound was prepared from m-chlorophenylacetic acid in 57%yield in the same manner as the preparation of2-(2-Chlorophenyl)propionic acid in Example 184a. MS (ESI) 185 (MH⁺).

b. N-(3-Chloro-3-trifluoromethylbenzyl)-2-(2-chlorophenyl)propionamide

The titled compound was prepared from 2-(3-Chlorophenyl)propionic acidin 22% yield in the same manner as the preparation ofN-(2-Chloro-3-trifluoromethylbenzyl)-2-(2-chlorophenyl)propionamide inExample 184b. MS (ESI) 376 (MH⁺).

c. N-(2-Chloro-3-trifluoromethylbenzyl)-2-(2-chlorophenyl)propylamine

The titled compound was prepared fromN-(2-chloro-3-trifluoromethylbenzyl)-2-(2-chlorophenyl)propionamide in61% yield in the same manner as the preparation ofN-(2-chloro-3-trifluoromethylbenzyl)-2-(2-chlorophenyl)propylamine inExample 184c. MS (ESI) 362 (MH⁺).

d.N-(2-[3-Chlorophenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carbomethoxymethylenephenoxy)propylamine

The titled compound was prepared fromN-(2-Chloro-3-trifluoromethylbenzyl)-2-(2-chlorophenyl)propylamine in49% yield in the same manner as the preparation ofN-(2-[2-Chlorophenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carbomethoxymethylenephenoxy)propylaminein Example 184f. MS (ESI) 568 (MH⁺).

e.N-(2-[3-Chlorophenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,hydrochloride

The titled compound was prepared fromN-(2-[3-Chlorophenyl]-propyl)-N(2-chloro-3-trifluoromethylbenzyl)-3-(3-carbomethoxymethylenephenoxy)propylaminein 48% yield in the same manner as the preparation ofN-(2-[2-Chlorophenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylaminein Example 184g. MS (ESI) 554 (MH⁺).

EXAMPLE 186N-(2-[4-Chlorophenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,hydrochloride

a. 2-(4-Chlorophenyl)propionic acid

The titled compound was prepared from p-chlorophenylacetic acid in 73%yield in the same manner as the preparation of2-(2-Chlorophenyl)propionic acid in Example 184a. MS (ESI) 185 (MH⁺).

b. N-(2-Chloro-3-trifluoromethylbenzyl)-2-(4-chlorophenyl)propionamide

The titled compound was prepared from 2-(4-Chlorophenyl)propionic acidin 32% yield in the same manner as the preparation ofN-(2-Chloro-3-trifluoromethylbenzyl)-2-(2-chlorophenyl)propionamide inExample 184b. MS (ESI) 376 (MH⁺).

c. N-(2-Chloro-3-trifluoromethylbenzyl)-2-(4-chlorophenyl)propylamine

The titled compound was prepared fromN-(2-chloro-3-trifluoromethylbenzyl)-2-(4-chlorophenyl)propionamide in94% yield in the same manner as the preparation ofN-(2-chloro-3-trifluoromethylbenzyl)-2-(2-chlorophenyl)propylamine inExample 184c. MS (ESI) 362 (MH⁺).

d.N-(2-[4-Chlorophenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carbomethoxymethylenephenoxy)propylamine

The titled compound was prepared fromN-(2-Chloro-3-trifluoromethylbenzyl)-2-(4-chlorophenyl)propylamine in33% yield in the same manner as the preparation ofN-(2-[2-Chlorophenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carbomethoxymethylenephenoxy)propylaminein Example 184f. MS (ESI) 568 (MH⁺).

e.N-(2-[4-Chlorophenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,hydrochloride

The titled compound was prepared fromN-(2-[4-Chlorophenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carbomethoxymethylenephenoxy)propylaminein 55% yield in the same manner as the preparation ofN-(2-(2-Chlorophenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylaminein Example 184g. MS (ESI) 554 (MH⁺).

EXAMPLE 187N-(2-[2-Methoxyphenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,hydrochloride

a. 2-(2-Methoxyphenyl)propionic acid

The titled compound was prepared from o-methoxyphenylacetic acid in 39%yield in the same manner as the preparation of2-(2-Chlorophenyl)propionic acid in Example 184a.

MS (ESI) 181 (MH⁺).

b. N-(2-Chloro-3-trifluoromethylbenzyl)-2-(2-methoxyphenyl)propionamide

The titled compound was prepared from 22-methoxyphenyl)propionic acid in42% yield in the same manner as the preparation ofN-(2-Chloro-3-trifluoromethylbenzyl)-2-(2-chlorophenyl)propionamide inExample 184b. MS (ESI) 372 (MH⁺).

c. N-(2-Chloro-3-trifluoromethylbenzyl)-2-(2-methoxyphenyl)propylamine

The titled compound was prepared fromN-(2-chloro-3-trifluoromethylbenzyl)-2-(2-methoxyphenyl)propionamide in28% yield in the same manner as the preparation ofN-(2-chloro-3-trifluoromethylbenzyl)-2-(2-chlorophenyl)propylamine inExample 184c. MS (ESI) 358 (MH⁺).

d.N-(2-[2-Methoxyphenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carbomethoxymethylenephenoxy)propylamine

The titled compound was prepared fromN-(2-Chloro-3-trifluoromethylbenzyl)-2-(2-methoxyphenyl)propylamine in90% yield in the same manner as the preparation ofN-(2-[2-Chlorophenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carbomethoxymethylenephenoxy)propylaminein Example 184f. MS (ESI) 564 (MH⁺).

e.N-(2-[2-Methoxyphenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,hydrochloride

The titled compound was prepared fromN-(2-[2-methoxyphenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carbomethoxymethylenephenoxy)propylaminein 62% yield in the same manner as the preparation ofN-(2-[2-Chlorophenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylaminein Example 184g. MS (ESI) 550 (MH⁺).

EXAMPLE 188N-(2-[4-Methoxyphenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,hydrochloride

a. 2-(4-Methoxyphenyl)propionic acid

The titled compound was prepared from p-methoxyphenylacetic acid in 73%yield in the same manner as the preparation of 22-chlorophenyl)propionicacid in Example 184a. MS (ESI) 181 (MH⁺)

b. 2-(4-Methoxyphenyl)propionamide

A solution of 2-(4-methoxyphenyl)propionic acid (230 mg, 1.28 mmole) in10 mL of benzene and 1 drop of DMF was treated with oxalyl chloride (0.5mL). The reaction was stirred at 23° for 1 hour, and the solvents wereevaporated. The residue was dissolved in 5 mL of Me₂CO and added to astirred mixture of 5 mL of Me₂CO and 5 mL of 28% NH₄OH. After 1 hour,the reaction was diluted with H₂O, and the solid filtered.Recrystallization from EtOH gave the titled compound, 146 mg (64%yield). MS (ESI) 181 (MH⁺)

c. 2-(4-Methoxyphenyl)propylamine, hydrochloride

A solution of 2-(4-methoxyphenyl)propionamide (550 mg, 3.07 mmole) in 15mL of THF was treated with BH₃ (15 mL of a 1N solution in THF), and thereaction was refluxed for 12 hours, cooled, and MeOH was added, and thesolvents were removed. The residue was dissolved in 5 mL of dioxane,treated with 10 mL of 6N HCl and refluxed for 2 hours. The reaction wascooled, diluted with H₂O, and washed with Et₂O. The aqueous layer wasbasified and extracted with Et₂O. The extracts were washed with H₂O,dried, and the solvent evaporated. The residue was converted to the HClsalt, and recrystallization from a mixture of Et₂O and isopropanol gavethe titled compound, 318 mg (52% yield). MS (ESI) 166 (MH⁺)

d. N-(2-Chloro-3-trifluoromethylbenzyl)-2-(4-methoxyphenyl)propylamine

A solution of 2-(4-methoxyphenyl)propylamine (183 mg, 1.11 mmole) and2-chloro-3-trifluoromethylbenzaldehyde (230 mg, 1.11 mmole) in 10 mL ofMeOH was treated with a crystal of p-toluenesulfonic acid hydrate, andstirred for 30 minutes. The reaction was diluted with Et₂O, and washedwith aqueous NaHCO₃. The extracts were dried, and the solvent removed. Asolution of the residue in 10 mL of MeOH was cooled to 0° and treatedwith excess NaBH4. The reaction was warmed to 23° and stirred for 30minutes. The reaction was diluted with H₂O and extracted with Et₂O. Theextracts were washed with H₂O, dried and the solvent removed, and gavethe titled compound, 305 mg (77% yield). MS (ESI) 358 (MH⁺)

e.N-(2-[4-Methoxyphenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carbomethoxymethylenephenoxy)propylamine

The titled compound was prepared fromN-(2-Chloro-3-trifluoromethylbenzyl)-2-(4-methoxyphenyl)propylamine in26% yield in the same manner as the preparation ofN-(2-[2-Chlorophenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carbomethoxymethylenephenoxy)propylaminein Example 184f. MS (ESI) 564 (MH⁺)

f.N-(2-[4-Methoxyphenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,hydrochloride

The titled compound was prepared fromN-(2-[4-methoxyphenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carbomethoxymethylenephenoxy)propylaminein 66% yield in the same manner as the preparation ofN-(2-[2-Chlorophenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylaminein Example 184g. MS (ESI) 550 (MH⁺)

EXAMPLE 189N-(2-Phenyl-4-methylpentyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,hydrochloride

a. Diethyl 2-phenyl-2-(2-methyl-2-propenyl)malonate

NaH (440 mg of a 60% dispersion in mineral oil, 11 mmole) was washedfree of mineral oil, and suspended in 20 mL of DMF. This was treatedwith a solution of diethyl phenylmalonate (2.36 g, 10 mmole) in 10 mL ofDMF, and the reaction was stirred for 15 minutes, at which time thesolution was clear. 2-Methylallyl bromide (2.0 mL) was added, andstirring continued for 1 hour. The reaction was diluted with H₂O andextracted with Et₂O. The extracts were washed with H₂O, dried and thesolvent removed and gave the titled compound, 2.85 g (95% yield). MS(ESI) 291 (MH⁺)

b. Methyl 2-phenyl-4-methyl-4-pentenoic acid

A solution of diethyl 2-phenyl-2-(2-methyl-2-propenyl)malonate (1.63 g,5.6 mmole) in 20 mL of EtOH and 5 mL of H₂O was treated with NaOH (2 g),and refluxed for 3 hours. The reaction was cooled, diluted with H₂O, andwashed with Et₂O. The aqueous layer was acidified and extracted withCH₂Cl₂. The extracts were dried and evaporated. The residue wasdissolved in 5 mL of dimethylacetamide and heated to 125° for 1 hour.The reaction was cooled, diluted with H₂O, acified, and extracted withEt₂O. The extracts were washed with H₂O, dried, and the solvent removed.The residue was dissolved in 10 mL of MEOH, a drop of concentrated H₂SO₄was added, and stirred for 24 hours. The reaction was diluted with H₂O,and extracted with Et₂O. The extracts were washed with H₂O, aqueousNaHCO₃, dried and the solvent removed, and gave the titled compound, 953mg (83%). MS (ESI) 205 (MH⁺)

c. 2-Phenyl-4-methylpentanoic acid

A solution of methyl 2-phenyl-4-methyl-4-pentenoic acid (850 mg, 4.15mmole) in 10 mL of MeOHwas treated with 5 mL of 2.5N NaOH and heated to50° for 30 minutes. The reaction was cooled, diluted with H₂O and washedwith Et₂O. The aqueous phase was acified, and extracted with CH₂Cl₂. Theextracts were washed with H₂O, dried and the solvent removed. Theresidue was dissolved in 25 mL of EtOAc, and hydrogenated over a 10%Pd/C catalyst, at 1 atmosphere H₂ pressure, for 2 hours. The catalystwas filtered and the solvent removed and gave the titled compound, 647mg (81%). MS (ESI) 193 (MH⁺)

d. 2-Phenyl-4-methylpentanoic acid amide

The titled compound was prepared from 2-phenyl-4-methylpentanoic acid in94% yield in the same manner as the preparation of2-(4-Methoxyphenyl)propionamide in Example 188b. MS (ESI) 192 (MH⁺)

e. 2-Phenyl-4-methylpentylamine

The titled compound was prepared from 2-phenyl-4-methylpentanoic acidamide in 51% yield in the same manner as the preparation of2-(4-methoxyphenyl)propylamine in Example 188c. MS (ESI) 178 (MH⁺)

f. N-(2-Chloro-3-trifluoromethylbenzyl)-2-phenyl-4-methylpentylamine

The titled compound was prepared from 2-Phenyl-4-methylpentylamine in77% yield in the same manner as the preparation ofN-(2-Chloro-3-trifluoromethylbenzyl)-2-(4-methoxyphenyl)propylamine inExample 188d. MS (ESI) 370 (MH⁺)

g.N-(2-Phenyl-4-methylpentyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carbomethoxymethylenephenoxy)propylamine

The titled compound was prepared fromN-(2-chloro-3-trifluoromethylbenzyl)-2-phenyl-4-methylpentylamine in 34%yield in the same manner as the preparation ofN-(2-[4-methoxyphenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carbomethoxymethylenephenoxy)propylaminein Example 188e. MS (ESI) 576 (MH⁺)

h.N-(2-Phenyl-4-methylpentyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,hydrochloride

The titled compound was prepared fromN-(2-phenyl-4-methylpentyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carbomethoxymethylenephenoxy)propylaminein 74% yield in the same manner as the preparation ofN-(2-[4-Methoxyphenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,hydrochloride in Example 188f. MS (ESI) 562 (MH⁺)

i.(R)-N-(2-Phenyl-4-methylpentyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,trifluoroacetate and(S)-N-(2-Phenyl-4-methylpentyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,trifluoroacetate

The enantiomers of racemicN-(2-Phenyl-4-methylpentyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylaminewere separated on a Chiralcel OJ Preparative HPLC column, 21 mm ID×250mm, elution with 25:75:0.1-EtOH:hexane:TFA, 15 ml/min.

EXAMPLE 190N-(2-Phenylbutyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,hydrochloride

a. The titled compound was prepared from 2-phenylbutylamine (Acta.Pharmaceutica Nordica (1992), 4(2), 105-9) in the same manner as thepreparation ofN-(2-Phenyl-4-methylpentyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,hydrochloride, Example 189 e-h. MS (ESI) 534 (MH⁺) b.(R)-N-2-Phenylbutyl)-N-(2-chloro-3-trifluormmethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,trifluoroacetate and(S)-N-(2-Phenylbutyl)-N-2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,trifluoroacetate

The enantiomers of racemicN-(2-phenylbutyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylaminewere separated on a Chiralcel OJ Preparative HPLC column, 21 mm ID×250mm, elution with 25:75:0.1-EtOH:hexane:TFA, 15 ml/min.

EXAMPLE 191N-(2-[2-Methyl-2-phenyl]propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,hydrochloride

The titled compound was prepared from 2-phenyl-2-methylpropylamine(Acta. Pharmaceutica Nordica (1992), 4(2), 105-9) in the same manner asthe preparation ofN-(2-Phenyl-4-methylpentyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,hydrochloride, Example 189e-h. MS (ESI) 534 (MH⁺)

EXAMPLE 192N-(2-Phenyl-3-methylbutyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,hydrochloride

The titled compound was prepared from 2-phenyl-3-methylbutylamine (Acta.Pharmaceutica Nordica (1992), 4(2), 105-9) in the same manner as thepreparation ofN-(2-Phenyl-4-methylpentyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,hydrochloride, Example 189e-h. MS (ESI) 548 (MH⁺).

EXAMPLE 193N-(2-Phenylhexyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,hydrochloride

The titled compound was prepared from 2-phenylhexylamine (J. Chem. Soc.Perk. Trans. 1: Organic and Biorganic Chemistry (1976), (1), 33-8) inthe same manner as the preparation ofN-(2-Phenyl-4-methylpentyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,hydrochloride, Example 189e-h. MS (ESI) 562 (MH⁺)

EXAMPLE 194N-(2-Phenyl-3-butynyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine

The titled compound was prepared from 2-ethynylphenethylamine (J. Med.Chem. (1988), 31(4), 704-6) in the same manner as the preparation ofN-(2-Phenyl-4-methylpentyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,hydrochloride, Example 189e-h. MS (ESI) 530 (MH⁺)

EXAMPLE 195(S)-N-(2-Phenyl-2-methoxyethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,hydrochloride

The titled compound was prepared from (S)-2-methoxyphenethyl amine (Eur.J. Med. Chem. (1995), 30(12), 949-54) in the same manner as thepreparation ofN-(2-Phenyl-4-methylpentyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,hydrochloride, Example 189e-h. MS (ESI) 536 (MH⁺)

EXAMPLE 196(R)-N-(2-Phenyl-2-methoxyethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,hydrochloride

The titled compound was prepared from (R)-2-methoxyphenethyl amine (Eur.J. Med. Chem. (1995), 30(12), 949-54) in the same manner as thepreparation ofN-(2-Phenyl-4-methylpentyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,hydrochloride, Example 189e-h. MS (ESI) 536 (MH⁺)

EXAMPLE 197(R)-N-(2-Phenyl-2-methoxyethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-[2-hydroxy-2-methylpropyl]phenoxy)propylamine

The titled compound was prepared from(R)-N-(2-phenyl-2-methoxyethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carbomethoxymethylenephenoxy)propylaminein 44% yield in the same manner as the preparation ofN-(2,2-Diphenylethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-[2-hydroxy-2-methylpropyl]phenoxy)propylaminein Example 182. MS (ESI) 550 (MH⁺)

EXAMPLE 1982-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2-methyl-propyl)amino]-propoxy}-phenyl)aceticacid hydrochloride salt

Following the procedure of Intermediate 1 (a)-(e) except isobutylaminewas used in step 1(b) instead of 2,2-diphenylethylamine the titlecompound was prepared as a white solid (7.5% overall). MS (ESI) 458.2(M+H⁺).

EXAMPLE 1991-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-cyclobutanecarboxylicacid hydrochloride salt

a)(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-aceticacid methyl ester

To a solution of(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-aceticacid (0.5 g, 3.7 mmol) in methanol (300 ml) was added concentratedhydrochloric acid (10 ml). After the resulting mixture was heated toreflux for 2 h solvent was removed under vacuum. The residue wasdissolved in water and neutralized to pH=7. The aqueous layer wasextracted with ethyl acetate. The combined organic layers were washedwith saturated sodium bicarbonate, brine, dried over sodium sulfate, andconcentrated in vacco to give the title compound as colorless oil (0.5g, 90%). MS m/e 596.6 (M+H)⁺.

b)1-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-cyclobutanecarboxylicacid methyl ester

To a solution of(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-aceticacid methyl ester (100 mg, 0.17 mmol) in dry THF (50 ml) was addedlithium diisopropylamide (1.26 ml, 0.5 mmol) dropwise with cooling to−78° C. After the reaction mixture was stirred at −78° C. for anadditional 1 h, diiodo-propane (152 mg, 0.51 mmol) was added. Thereaction was warmed to room temperature over 4 h followed by quenchingwith saturated ammonium chloride (10 ml). Solvent was removed and theresidue was partitioned between water and ethyl acetate. The combinedorganic layers were washed with brine, dried over sodium sulfate andconcentrated under vacuum. The residue was purified by silica gel columnchromatograph (EtOAc:Hexane/20:80) to give the title compound as an oil(40 mg, 50%). MS m/e 636.2 (M+H)⁺.

c)1-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-cyclobutanecarboxylicacid hyrdochloride salt

A solution of1-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-cyclobutanecarboxylicacid methyl ester (40 mg, 0.06 mmol) in DMF (9 ml) was treated with LiCl(20 mg, 0.46 mmol). The resulting reaction mixture was heated to refluxovernight and concentrated under vacuum. The crude product was purifiedby HPLC (YMC CombiPrep ODS-A, 50×20 mm, 20 mL/min, A: acetonitrile B:water, A: 60 to 100% during 10 min, W detection at 254 nm) to give thetitle compound, the free amine as an oil (20 mg, 50%). MS m/e 622.2(M+H)⁺. To a solution of the free amine in diethyl ether was added HClin diethyl ether (1.0M) to precipitate the amine salt. The suspensionwas filtered and dried to give the title compound as a white solid.

EXAMPLE 2001-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-cyclopentanecarboxylicacid hydrochloride salt

Following the procedure of Example 199 except substituting1,4-diiodo-butane for iodoethane in step b, the title compound wasobtained as a white solid (15 mg, 35%). MS (ESI): 637.2 (M+H)⁺.

EXAMPLE 2011-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-cyclopropanecarboxylicacid hydrochloride salt

a) (3-Benzyloxy-phenyl)-acetic acid methyl ester

To a solution of 3-phenoxy-acetic acid methyl ester (2.0 g, 12 mmol) indry acetone (60 mL) with potassium carbonate (3.3 g, 24 mmol) was addedbenzylbromide (2.1 ml, 18 mmol). The reaction mixture was heated toreflux for 1 h. After cooling, the solvent was evaporated, water wasadded and the organic products were extracted into ethyl acetate, washedwith brine, dried (MgSO4), and evaporated. The residue was purified bycolumn chromatography over silica gel (silica gel 60, EM Science) usinga gradient of 5-30% ethyl acetate:hexane as eluent to afford 2.1 g (66%yield) of the title compound as an oil. ¹H NMR (CDCl₃, 400 MHz) δ7.45-7.25 (m, 6 H), 6.95-6.90 (m, 3 H), 5.09 (s, 2 H), 3.72 (s, 3 H),3.63 (s, 2 H).

b) 2-(3-Benzyloxy-phenyl)-3-oxo-succinic acid diethyl ester

Intermediates b-c were prepared following the procedure of Jefford, C.W.; Kubota, T.; Zaslona, A. Helvetica Chimica Acta 1986, 69(8),2048-2061. Dry ethanol (4 ml) was added to sodium (120 mg) while coolingto 0 C. After the bubbling ceased, diethyl oxylate (532 uL, 3.9 mmol)was added in ethanol (1 ml) followed by (3-Benzyloxy-phenyl)-acetic acidmethyl ester (1.0 g, 3.9 mmol). This mixture was stirred and allowed towarm to RT overnight. The solvent was evaporated, the residue taken upin water and diethyl ether. The aqueous layer was collected andneutralized, then the product was extracted into methylene chloridewhich was dried (MgSO4), and evaporated to afford 1.28 g (89% yield) ofthe title compound as an oil: MS (ESI) 371.2 (M+H⁺).

c) 2-(3-Benzyloxy-phenyl)-acrylic acid ethyl ester

To 2-(3-Benzyloxy-phenyl)-3-oxo-succinic acid diethyl ester (1.28 g, 3.6mmol) in water (5 ml) was added formaldehyde (600 uL, 37% solution, 6.6mmol) and potassium carbonate (0.37 g, 2.7 mmol). The reaction wasstirred vigorously overnight The organic products were extracted intodiethyl ether which was dried (MgSO4), and evaporated. The residue waspurified by column chromatography over silica gel (silica gel 60, EMScience) using 5% ethyl acetate:hexane as eluent to afford 0.99 g (55%yield) of the title compound as an oil. ¹H NMR (CDCl₃, 400 MHz) δ7.48-7.27 (m, 6H), 7.10-6.97 (m, 3H), 6.35 (s, 1H), 5.90 (s, 1H), 5.10(s, 2H), 4.30 (q, J=7.2 Hz, 2H), 1.36 (t, J=7.2 Hz, 3H).

d) 1-(3-Benzyloxy-phenyl)-2,2-dibromo-cyclopropanecarboxylic acid ethylester

Intermediates d-e were prepared following the procedure of Kirmse, W.;Rode, J. Chem. Ber. 1986, 119, 3694-3703. To absolution of2-(3-benzyloxy-phenyl)-acrylic acid ethyl ester (250 mg, 0.89 mmol) inmethylene chloride (283 uL) was added bromoform (100 uL, 1.1 mmol),benzyltriethyl ammonium chloride (2.6 mg), and sodium hydroxide (50%aqueous solution, 167 uL). The reaction was stirred at room temperaturefor 48 hours and then the product was extracted into diethyl ether,dried (MgSO4), and evaporated. This material was further purified byfiltration through a plug of silica gel using diethyl ether as theeluant to give 358 mg (89% yield) of the title compounds as a whitesolid. MS (ESI) 454.8 (M+H⁺).

e) 1-(3-Hydroxy-phenyl)-cyclopropanecarboxylic acid ethyl ester

To a solution of1-(3-Benzyloxy-phenyl)-2,2-dibromo-cyclopropanecarboxylic acid ethylester (282 mg, 0.62 mmol) in diethyl ether (1 ml) was added tributyltinhydride (420 uL, 1.5 mmol). Additional tin was added with stirring over48 hours to try to push the reaction to completion. After evaporation,purification by column chromatography over silica gel (silica gel 60, EMScience) using a gradient of 1-5% ethyl acetate:hexane as eluent wasused to afford 200 mg of 13-Benzyloxy-phenyl)-cyclopropanecarboxylicacid ethyl ester and a mono-brominated contaminant as an oil: MS (ESI)297.2 (M+H⁺).

To this mixture was added palladium on carbon (10 w %, 100 mg), methanol(10 ml), and hydrogen was applied at 50 psi using a parr shaker over 4hours. The reaction was filtered through celite and the solventevaporated. The residue was purified by preparative HPLC (YMC CombiPrepODS-A, 50×20 mm, 20 mL/min, A: acetonitrile B: water, A: 10 to 90%during 10 min, UV detection at 254 nm) to give 25 mg (20% over 2 steps)of the title compound as an oil. MS (ESI) 207.0 [M+H]⁺.

f) (2-Chloro-3-trifluoromethyl-benzyl)-diphenyl

To a solution of 2,2-Diphenyl-ethylamine (1.149, 5.7 mmol) in drydichloromethane (300 ml) was added acetic acid followed by2-chloro-3-trifluoromethylbenzaldehyde (1.0 g, 4.8 mmol) and sodiumtriacetoxyborohydride (2.03 g, 9.6 mmol). After the resulting mixturewas stirred for 1.5 h at room temperature water was added to quench thereaction. The aqueous layer was extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over sodiumsulfate, and concentrated in vacco. The crude mixture was purified bysilica gel column chromatograph (EtOAc:Hexane/25:75) to give the titlecompound as an oil 1.7 g. (yield 76%). MS m/e 387.2 (M+H)⁺.

g)(3-Bromo-propyl)-(2-chloro-3-trifluoromethyl-benzyl)diphenylethyl-amine

A solution of compound(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amine (2.5 g, 6.5mmol) and 1,3-dibromo propane (3.2 ml, 32 mmol) in acetonitrile (300 ml)was treated with solid potassium carbonate (1.8 g, 13 mmol). Thereaction was heated to reflux and stirred for 48 h. Upon cooling to roomtemperature, the reaction was filtered through a pad of celite, washedwith EtOAc, and the filtrate was concentrated in vacuo. The crudeproduct was purified by column chromatography (EtOAc:Hexane/20:80) togive the title compound as an oil (2.2 g, 67%). MS m/e 510.6 (M+H)⁺.

h)1-(3-{3-[3-Chloro-2-trifluoromethyl-benzyl-(2,2-diphenyl-ethyl)-amino]-propoxy)phenyl)-cyclopropanecarboxylicacid ethyl ester

To a solution of 1-(3-Hydroxy-phenyl)-cyclopropanecarboxylic acid ethylester (25 mg, 0.12 mmol) in acetonitrile (2 ml) was added potassiumcarbonate (37 mg, 0.24 mmol) and(3-Bromo-propyl)-(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amine(68 mg, 0.13 mmol). The mixture was heated to reflux overnight Aftercooling, the solvent was evaporated, water was added and the organicproducts were extracted into ethyl acetate, washed with brine, dried(MgSO4), and evaporated. Further purification by column chromatographyover silica gel (silica gel 60, EM Science) using 5% ethylacetate:hexane as eluent was used to afford 65 mg (84% yield) of thetitled compound as an oil: MS (ESI) 636.2 (M+H⁺).

i)1-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-cyclopropanecarboxylicacid hydrochloride salt

To a solution of1(3-{3-[2-Chloro-3-trifluoromethyl-benzyl-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-cyclopropanecarboxylicacid ethyl ester (65 mg, 0.12 mmol) in THF (1 ml) and methanol (4 ml)was added lithium hydroxide (2N aq., 1 ml). The reaction was stirred atRT overnight. Acidic water was added to neutralize the solution and theorganic products were extracted into ethyl acetate, washed with brine,dried (MgSO4), and evaporated. The residue was purified by preparativeHPLC (YMC CombiPrep ODS-A, 50×20 mm, 20 mL/min, A: acetonitrile B:water, A: 10 to 90% during 10 min, UV detection at 254 nm) to give 17 mg(27%) of the title compound as an oil. The oil was dissolved inmethanol, and HCl in diethyl ether was added, the solvents wereevaporated to form the hydrochloride salt as a solid. MS (ESI) 608.0[M+H]⁺.

The above description fully discloses how to make and use the presentinvention. However, this invention is not limited to the particularembodiments described hereinabove, but includes all modification thereofwithin the scope of the appended claims and their equivalents. Thoseskilled in the art will recognize through routine experimentation thatvarious changes and modifications can be made without departing from thescope of this invention. The various references to journals, patents andother patent applications that are cited herein are incorporated byreference herein as though fully set forth.

1. A compound of Formula I:

wherein: X is selected from C₁-C₈ alkyl, halo, —OR¹⁰, —NR¹⁴R¹⁵, nitro,cyano, —COOR¹⁰, —COR¹³, —OCOR¹³, —N(R¹⁷)COR¹³, —N(R¹⁷)CONR¹⁴R¹⁵,—N(R¹⁷)COOR¹³, —SO₃H, —SO₂NR¹⁴R¹⁵, —C(═NR¹⁷)NR¹⁴R¹⁵, —N(R¹⁷)SO₂R¹⁶, anda 5 or 6-membered heterocyclic group; or X and an adjacent R³, takentogether with the atoms to which they are bonded, form an alkylenedioxymoiety; Z is CH, CR³ or N, wherein when Z is CH or CR³, k is 0-4 and tis 0 or 1, and when Z is N, k is 0-3 and t is 0; Y is selected from —O—,—S—, —N(R¹⁰)-, and —C(R⁴)(R⁵)—; W¹ is selected from C₃-C₈ cycloalkyl,aryl and Het, wherein said C₃-C₈ cycloalkyl, aryl and Het are optionallyunsubstituted or substituted with one or more groups independentlyselected from halo, cyano, nitro, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆alkynyl, —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆ alkyl-C(O)SR¹⁰, —C₀-C₆alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆ alkyl-NR¹¹R¹², —C₀-C₆alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-SO₃H, —C₀-C₆alkyl-SO₂NR¹¹R¹², —C₀-C₆ alkyl-SO₂R¹⁰, —C₀-C₆ alkyl-SOR¹³, —C₀-C₆alkyl-OCOR¹³, —C₀-C₆ alkyl-OC(O)NR¹¹R¹², —C₀-C₆ alkyl-OC(O)OR¹³, —C₀-C₆alkyl-NR¹¹C(O)OR¹³, —C₀-C₆ alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₆alkyl-NR¹¹COR¹³, where said C₁-C₆ alkyl, is optionally unsubstituted orsubstituted by one or more halo substituents; W² is selected from H,halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —C₀-C₆ alkyl-NR¹¹R¹²,—C₀-C₆ alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆alkyl-C(O)SR¹⁰, —C₀-C₆ alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆alkyl-OCOR¹³, —C₀-C₆ alkyl-OCONR¹¹R¹², —C₀-C₆ alkyl-NR¹¹CONR¹¹R¹²,—C₀-C₆ alkyl-NR¹¹COR¹³, —C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-aryl and —C₀-C₆alkyl-C₃-C₇ cycloalkyl, wherein said C₁-C₆ alkyl is optionallyunsubstituted or substituted by one or more halo substituents, andwherein the C₃-C₇ cycloalkyl, aryl and Het moieties of said —C₀-C₆alkyl-Het, —C₀-C₆ alkyl-aryl and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl areoptionally unsubstituted or substituted with one or more groupsindependently selected from halo, cyano, nitro, C₁-C₆ alkyl, C₃-C₆alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆ alkyl-C(O)SR¹⁰,—C₀-C₆ alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆ alkyl-NR¹¹R¹², —C₀-C₆alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-SO₃H, —C₀-C₆alkyl-SO₂NR¹¹R¹², —C₀-C₆ alkyl-SO₂R¹⁰, —C₀-C₆ alkyl-SOR¹³, —C₀-C₆alkyl-OCOR¹³, —C₀-C₆ alkyl-OC(O)NR¹¹R¹², —C₀-C₆ alkyl-OC(O)OR¹³, —C₀-C₆alkyl-NR¹¹C(O)OR¹³, —C₀-C₆ alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₆alkyl-NR¹¹COR¹³, where said C₁-C₆ alkyl, is optionally unsubstituted orsubstituted by one or more halo substituents; W³ is selected from thegroup consisting of: H, halo, C₁-C₆ alkyl, —C₀-C₆ alkyl-NR¹¹R¹², —C₀-C₆alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆alkyl-C(O)SR¹⁰, —C₀-C₆ alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆alkyl-OCOR¹³, —C₀-C₆ alkyl-OCONR¹¹R¹², —C₀-C₆ alkyl-NR¹¹CONR¹¹R¹²,—C₀-C₆ alkyl-NR¹¹COR¹³, —C₀-C₆ alkyl-Het, —C₁-C₆ alkyl-aryl and —C₁-C₆alkyl-C₃-C₇ cycloalkyl, wherein said C₁-C₆ alkyl is optionallyunsubstituted or substituted by one or more halo substituents; Q isselected from C₃-C₈ cycloalkyl, Ar and Het; wherein said C₃-C₈cycloalkyl, Ar and Het are optionally unsubstituted or substituted withone or more groups independently selected from halo, cyano, nitro, C₁-C₆alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆alkyl-C(O)SR¹⁰, —C₀-C₆ alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆alkyl-NR¹¹R¹², —C₀-C₆ alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-SO₃H,—C₀-C₆ alkyl-SO₂NR¹¹R¹², —C₀-C₆ alkyl-SO₂R¹⁰, —C₀-C₆ alkyl-SOR¹³, —C₀-C₆alkyl-OCOR¹³, —C₀-C₆ alkyl-OC(O)NR¹¹R¹², —C₀-C₆ alkyl-OC(O)OR¹³, —C₀-C₆alkyl-NR¹¹C(O)OR¹³, —C₀-C₆ alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₆alkyl-NR¹¹COR¹³, where said C₁-C₆ alkyl is optionally unsubstituted orsubstituted by one or more halo substituents; p is 0-8; n is 3; m is 0or 1; q is 0 or 1; t is 0 or 1; each R¹ and R² are independentlyselected from H, halo, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆alkyl-NR¹¹R¹², —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-SR¹⁰, —C₁-C₆ alkyl-Het,—C₁-C₆ alkyl-Ar and —C₁-C₆ alkyl-C₃-C₇ cycloalkyl, or R¹ and R² togetherwith the carbon to which they are attached form a 3-5 memberedcarbocyclic or heterocyclic ring, wherein said heterocyclic ringcontains one, or more heteroatoms selected from N, O, and S, where anyof said C₁-C₆ alkyl is optionally unsubstituted or substituted by one ormore halo substituents; each R³ is the same or different and isindependently selected from halo, cyano, nitro, C₁-C₆ alkyl, C₃-C₆alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-Ar, —C₀-C₆ alkyl-Het, —C₀-C₆alkyl-C₃-C₇ cycloalkyl, —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆ alkyl-C(O)SR¹⁰,—C₀-C₆ alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆ alkyl-NR¹¹R¹², —C₀-C₆alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-SO₃H, —C₀-C₆alkyl-SO₂NR¹¹R¹², —C₀-C₆ alkyl-SO₂R¹⁰, —C₀-C₆ alkyl-SOR¹³, —C₀-C₆alkyl-OCOR¹³, —C₀-C₆ alkyl-OC(O)NR¹¹R¹², —C₀-C₆ alkyl-OC(O)OR¹³, —C₀-C₆alkyl-NR¹¹C(O)OR¹³, —C₀-C₆ alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₆alkyl-NR¹¹COR¹³, wherein said C₁-C₆ alkyl is optionally unsubstituted orsubstituted by one or more halo substituents; each R⁴ and R⁵ isindependently selected from H, halo, C₁-C₆ alkyl, —C₀-C₆ alkyl-Het,—C₀-C₆ alkyl-Ar and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl; R⁶ and R⁷ are eachindependently selected from H, halo, C₁-C₆ alkyl, —C₀-C₆ alkyl-Het,—C₀-C₆ alkyl-Ar and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl; R⁸ and R⁹ are eachindependently selected from H, halo, C₁-C₆ alkyl, —C₀-C₆ alkyl-Het,—C₀-C₆ alkyl-Ar and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl; R¹⁰ is selected fromH, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-Ar, —C₀-C₆alkyl-Het and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl; each R¹¹ and each R¹² areindependently selected from H, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆alkynyl, —C₀-C₆ alkyl-Ar, —C₀-C₆ alkyl-Het and —C₀-C₆ alkyl-C₃-C₇cycloalkyl, or R¹¹ and R¹² together with the nitrogen to which they areattached form a 4-7 membered heterocyclic ring which optionally containsone or more additional heteroatoms selected from N, O, and S; R¹³ isselected from C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆alkyl-Ar, —C₀-C₆ alkyl-Het and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl; R¹⁴ andR¹⁵ are each independently selected from H, C₁-C₆ alkyl, C₃-C₆ alkenyl,C₃-C₆ alkynyl, —C₀-C₆ alkyl-Ar, —C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-C₃-C₇cycloalkyl, —C₀-C₆ alkyl-O—Ar, —C₀-C₆ alkyl-O-Het, —C₀-C₆ alkyl-O—C₃-C₇cycloalkyl, —C₀-C₆ alkyl-S(O)_(x)—C₁-C₆ alkyl, —C₀-C₆ alkyl-S(O)_(x)—Ar,—C₀-C₆ alkyl-S(O)_(x)-Het, —C₀-C₆ alkyl-S(O)_(x)—C₃-C₇ cycloalkyl,—C₀-C₆ alkyl-NH-Het, —C₀-C₆ alkyl-NH—C₃-C₇ cycloalkyl, —C₀-C₆alkyl-N(C₁-C₄ alkyl)-Ar, —C₀-C₆ alkyl-N(C₁-C₄ alkyl)-Het, —C₀-C₆alkyl-N(C₁-C₄ alkyl)-C₃-C₇ cycloalkyl, —C₀-C₆ alkyl-Ar, —C₀-C₆ alkyl-Hetand —C₀-C₆ alkyl-C₃-C₇ cycloalkyl, where x is 0, 1 or 2, or R¹⁴ and R¹⁵,together with the nitrogen to which they are attached, form a 4-7membered heterocyclic ring which optionally contains one or moreadditional heteroatoms selected from N, O, and S, wherein said C₁-C₆alkyl is optionally substituted by one or more of the substituentsindependently selected from the group halo, —OH, —SH, —NH₂,—NH(unsubstituted C₁-C₆ alkyl), —N(unsubstituted C₁-C₆alkyl)(unsubstituted C₁-C₆ alkyl), unsubstituted —OC₁-C₆ alkyl, —CO₂H,—CO₂(unsubstituted C₁-C₆ alkyl), —CONH₂, —CONH(unsubstituted C₁-C₆alkyl), —CON(unsubstituted C₁-C₆ alkyl)(unsubstituted C₁-C₆ alkyl),—SO₃H, —SO₂NH₂, —SO₂NH(unsubstituted C₁-C₆ alkyl) and—SO₂N(unsubstituted C₁-C₆ alkyl)(unsubstituted C₁-C₆ alkyl); R¹⁶ isC₁-C₆ alkyl, —C₀-C₆ alkyl-Ar or —C₀-C₆ alkyl-Het; and R¹⁷ is H, C₁-C₆alkyl, —C₀-C₆ alkyl-Ar or —C₀-C₆ alkyl-Het; wherein each Ar or arylindependently represent a substituted or unsubstituted carbocyclicaromatic group, which may be optionally fused to another carbocyclicaromatic group moiety or to a cycloalkyl group moiety, wherein said Aror aryl is optionally substituted by one or more of the substituentsindependently selected from the group halo, cyano, C₁-C₆ alkyl, C₁-C₆haloalkyl, —C₀-C₆ alkyl-OH, —C₀-C₆ alkyl-SH, —C₀-C₆ alkyl-NR′R″, C₃-C₆alkenyl, —OC₁-C₆alkyl, —OC₁-C₆ alkenyl, —C₀-C₆ alkyl-COR′, —C₀-C₆alkyl-CO₂R′, —C₀-C₆ alkyl-CONR′R″, —OC₀-C₆ alkyl-CO₂H, —OC₂-C₆alkyl-NR′R″, —C₀-C₆ alkyl-C(═NR′)NR′R″, and —C₀-C₆ alkyl-SO₂NR′R″,wherein each R′ and R″ are independently selected from H andunsubstituted C₁-C₆ alkyl, each Het independently represents amonocyclic 5- to 7-membered, a bicyclic 7- to 10-membered or a tricyclic11- to 18-membered heterocyclic ring group which is saturated,unsaturated or aromatic, and consists of carbon atoms and from one tothree heteroatoms selected from N, O and S, wherein the N or Sheteroatoms of said Het are optionally oxidized or the N heteroatom isoptionally quaternized, wherein said Het is optionally unsubstituted orsubstituted by one or more of the substituents independently selectedfrom the group halo, cyano, C₁-C₆ alkyl (which specifically includesC₁-C₆ haloalkyl, —C₀-C₆ alkyl-OH, —C₀-C₆ alkyl-SH and —C₀-C₆alkyl-NR′R″), C₃-C₆ alkenyl, oxo, —OC₁-C₆alkyl, —OC₁-C₆ alkenyl, —C₀-C₆alkyl-COR′, —C₀-C₆ alkyl-CO₂R′, —C₀-C₆ alkyl-CONR′R″, —OC₀-C₆alkyl-CO₂H, —OC₂-C₆ alkyl-NR′R″, —C₀-C₆ alkyl-C(═NR′)NR′R″ and —C₀-C₆alkyl-SO₂NR′R″, wherein each R′ and R″ are independently selected from Hand unsubstituted C₁-C₆ alkyl; provided that X is not COOR¹⁰ when Y is—O—, p is 0-8, n is 3, m is 1, q is 0 or 1, t is 0, each R¹ and R² isindependently selected from H, C₁-C₆ alkyl, —OH, —O—C₁-C₆ alkyl, —SH,and —S—C₁-C₆ alkyl, each R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are independently Hor C₁-C₄ alkyl, k is 0 or 1, W³ is H, W¹ and W² are each independentlyselected from C₃-C₈ cycloalkyl and aryl and R³ and Q are as definedabove; or provided that the compound is not5-[3-[[(3,4-dichlorophenyl)methyl][2-(2-naphthalenyl)ethyl]amino]propoxy]-3-methoxy-1,2-benzenedicarboxylicacid, or5-[3-[[(3,4-dichlorophenyl)methyl][2-(2-naphthalenyl)ethyl]amino]propoxy]-3-methoxy-1,2-benzenedicarboxylicacid, dimethyl ester; or a pharmaceutically acceptable salt or hydratethereof.
 2. The compound according to claim 1, wherein p is 0, 1 or 2.3. The compound according to claim 1, wherein t is
 0. 4. The compoundaccording to claim 1, wherein R¹ and R² are independently H or C₁-C₄alkyl or R¹ and R² together with the carbon to which they are attachedform a 3-5 membered carbocyclic ring.
 5. The compound according to claim1, wherein k is 0 or
 1. 6. The compound according to claim 1, wherein R³is selected from halo, C₁-C₄ alkyl and C₁-C₄ alkoxy.
 7. The compoundaccording to claim 1, wherein X is selected from C₁-C₆ alkyl, halo,—OR¹⁰, —NR¹⁴R¹⁵, cyano, —COR¹³, —COOR¹⁰, —OCOR¹³, —N(R¹⁷)CONR¹⁴R¹⁵,—N(R¹⁷)COR¹³, —SO₂NR¹⁴R¹⁵, —N(R¹⁷)SO₂R¹⁶, and a 5 or 6-memberedheterocyclic group or X and an adjacent R³, taken together with theatoms to which they are bonded, form an alkylenedioxy moiety.
 8. Thecompound according to claim 7, wherein R¹⁰ is H, C₁-C₄ alkyl or phenyl;R¹³ is H, C₁-C₄ alkyl, —C₀-C₄ alkyl-C₃-C₇ cycloalkyl, or —C₀-C₄alkyl-phenyl; R¹⁴ and R¹⁵ are each independently selected from H, C₁-C₆alkyl, —C₀-C₄ alkyl-Ar, —C₀-C₄ alkyl-Het, —C₀-C₄ alkyl-C₃-C₇ cycloalkyl,—C₀-C₄ alkyl-O—Ar, —C₀-C₄ alkyl-O-Het, —C₀-C₄ alkyl-O—C₃-C₇ cycloalkyl,—C₀-C₄ alkyl-S(O)₂—C₁-C₄ alkyl, —C₀-C₄ alkyl-S(O)₂—Ar, —C₀-C₄alkyl-S(O)₂-Het, —C₀-C₄ alkyl-S(O)₂—C₃-C₇ cycloalkyl, —C₀-C₄alkyl-NH—Ar, —C₀-C₄ alkyl-NH-Het, —C₀-C₄ alkyl-NH—C₃-C₇ cycloalkyl,—C₀-C₄ alkyl-N(C₁-C₄ alkyl)-Ar, —C₀-C₄ alkyl-N(C₁-C₄ alkyl)-Het, —C₀-C₄alkyl-N(C₁-C₄ alkyl)-C₃-C₇ cycloalkyl, —C₀-C₄ alkyl-Ar, —C₀-C₄ alkyl-Hetand —C₀-C₄ alkyl-C₃-C₇ cycloalkyl, or R¹⁴ and R¹⁵, together with thenitrogen to which they are attached, form a 4-7 membered heterocyclicring which optionally contains one or more additional heteroatomsselected from N, O, and S, wherein said C₁-C₆ alkyl is optionallysubstituted by one or more of the substituents independently selectedfrom the group halo, —OH, —SH, —NH₂, —NH(unsubstituted C₁-C₄ alkyl),—N(unsubstituted C₁-C₄ alkyl)(unsubstituted C₁-C₄ alkyl), unsubstituted—OC₁-C₄ alkyl, —CO₂H, —CO₂(unsubstituted C₁-C₄ alkyl), —CONH₂,—CONH(unsubstituted C₁-C₄ alkyl), —CON(unsubstituted C₁-C₄alkyl)(unsubstituted C₁-C₄ alkyl), —SO₃H, —SO₂NH₂, —SO₂NH(unsubstitutedC₁-C₄ alkyl) and —SO₂N(unsubstituted C₁-C₄ alkyl)(unsubstituted C₁-C₄alkyl); R¹⁶ is C₁-C₄ alkyl or phenyl; and R¹⁷ is H or C₁-C₄ alkyl. 9.The compound according to claim 1 wherein each R⁴ and R⁵ areindependently selected from H and C₁-C₃ alkyl.
 10. The compoundaccording to claim 1, wherein R⁸ and R⁹ are each H.
 11. The compoundaccording to claim 1, wherein Q is a substituted or unsubstituted phenylor furanyl group or a benzo[1,3]dioxyl or benzo[1,4]dioxyl groupcontaining one, two or three substituents selected from halo, C₁-C₄alkyl; C₁-C₄ alkylthio; or —NR^(Q1)R^(Q2), where R^(Q1) and R^(Q2) takentogether with the nitrogen to which they are attached form a 4-7membered heterocyclic ring, which may optionally contain one or moreadditional heteroatoms selected form N, O and S.
 12. The compoundaccording to claim 11, wherein said substituents are selected fromfluoro, chloro, trifluoromethyl, tert-butyl, isopropyl, methylthio andpiperidin-1-yl.
 13. The compound according to claim 1, wherein m is 0 orm is 1 and R⁶ and R⁷ are each H.
 14. The compound according to claim 1,wherein W¹ is phenyl, naphthyl, thienyl, pyridyl, furanyl, pyrrolyl,cyclohexyl, cyclopentyl, morpholinyl, or pyrrolidinyl, where eachphenyl, naphthyl, thienyl, pyridyl, furanyl, pyrrolyl, cyclohexyl,cyclopentyl, morpholinyl, or pyrrolidinyl may be optionally substitutedfrom 1 to 3 times with one or more of the substituents independentlyselected from C₁-C₄ alkyl, —OH, halo, —O—C₁-C₄ alkyl, and —C₁-C₄haloalkyl.
 15. The compound according to claim 1, wherein W² is C₁-C₄alkyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, aryl, Het hydroxy, aryloxy-,C₁-C₄ alkoxy-, —OCOC₁-C₄ alkyl, —OCOaryl, or —NR^(W1)R^(W2), whereR^(W1) and R^(W2) are independently H or C₁-C₄ alkyl or taken togetherwith the nitrogen to which they are attached form a 4-7 memberedheterocyclic ring, which may optionally contain one or more additionalheteroatoms selected form N, O and S.
 16. The compound according toclaim 1, wherein W³ is H or C₁-C₄ alkyl.
 17. The compound according toclaim 1, wherein X is selected from C₁-C₆ alkyl, halo, —OR¹⁰, —NR¹⁴R¹⁵,cyano, —COR¹³, —COOR¹⁰, —OCOR¹³, —N(R¹⁷)CONR¹⁴R¹⁵, —N(R¹⁷)COR¹³,—SO₂NR¹⁴R¹⁵, —N(R¹⁷)SO₂R¹⁶, and a 5 or 6-membered heterocyclic group orX and an adjacent R³, taken together with the atoms to which they arebonded, form an alkylenedioxy moiety, where R¹⁰ is H, C₁-C₄ alkyl orphenyl, R¹³ is H, C₁-C₄ alkyl, —C₀-C₄ alkyl-C₃-C₇ cycloalkyl, or —C₀-C₄alkyl-phenyl, R¹⁴ and R¹⁵ are each independently selected from H, C₁-C₆alkyl, —C₀-C₄ alkyl-Ar, —C₀-C₄ alkyl-Het, —C₀-C₄ alkyl-C₃-C₇ cycloalkyl,—C₀-C₄ alkyl-O—Ar, —C₀-C₄ alkyl-O-Het, —C₀-C₄ alkyl-O—C₃-C₇ cycloalkyl,—C₀-C₄ alkyl-S(O)₂-C₁-C₄ alkyl, —C₀-C₄ alkyl-S(O)₂—Ar, —C₀-C₄alkyl-S(O)₂-Het, —C₀-C₄ alkyl-S(O)₂-C₃-C₇ cycloalkyl, —C₀-C₄alkyl-NH—Ar, —C₀-C₄ alkyl-NH-Het, —C₀-C₄ alkyl-NH—C₃-C₇ cycloalkyl,—C₀-C₄ alkyl-N(C₁-C₄ alkyl)-Ar, —C₀-C₄ alkyl-N(C₁-C₄ alkyl)-Het, —C₀-C₄alkyl-N(C₁-C₄ alkyl)-C₃-C₇ cycloalkyl, —C₀-C₄ alkyl-Ar, —C₀-C₄ alkyl-Hetand —C₀-C₄ alkyl-C₃-C₇ cycloalkyl, or R¹⁴ and R¹⁵, together with thenitrogen to which they are attached, form a 4-7 membered heterocyclicring which optionally contains one or more additional heteroatomsselected from N, O, and S, wherein said C₁-C₆ alkyl is optionallysubstituted by one or more of the substituents independently selectedfrom the group halo, —OH, —SH, —NH₂, —NH(unsubstituted C₁-C₄ alkyl),—N(unsubstituted C₁-C₄ alkyl)(unsubstituted C₁-C₄ alkyl), unsubstituted—OC₁-C₄ alkyl, —CO₂H, —CO₂(unsubstituted C₁-C₄ alkyl), —CONH₂,—CONH(unsubstituted C₁-C₄ alkyl), —CON(unsubstituted C₁-C₄alkyl)(unsubstituted C₁-C₄ alkyl), —SO₃H, —SO₂NH₂, —SO₂NH(unsubstitutedC₁-C₄ alkyl) and —SO₂N(unsubstituted C₁-C₄ alkyl)(unsubstituted C₁-C₄alkyl), R¹⁶ is C₁-C₄ alkyl or phenyl, and R¹⁷ is H or C₁-C₄ alkyl; p is0, 1 or 2; R¹ and R² are independently H or C₁-C₄ alkyl or R¹ and R²together with the carbon to which they are attached form a 3-5 memberedcarbocyclic ring; k is 0 or k is 1 and R³ is halo, C₁-C₄ alkyl or C₁-C₄alkoxy; n is 3 and each R⁴ and R⁵ are independently selected from H andC₁-C₃ alkyl; Z is CH or N; Y is —O— or —C(R⁴)(R⁵)—; q is 1; R⁸ and R⁹are each H; Q is a substituted or unsubstituted phenyl or furanyl groupor a benzo[1,3]dioxyl or benzo[1,4]dioxyl group, where the substitutedphenyl or furanyl group contains one, two or three substituents selectedfrom halo, C₁-C₄ alkyl; C₁-C₄ alkylthio; or —NR^(Q1)R^(Q2), where R^(Q1)and R^(Q2) taken together with the nitrogen to which they are attachedform a 4-7 membered heterocyclic ring, which may optionally contain oneor more additional heteroatoms selected form N, O and S; t is 0 or 1; mis 0 or 1; R⁶ and R⁷ are independently selected from H and C₁-C₄ alkyl;W¹ is unsubstituted phenyl, naphthyl, pyridyl, thienyl or pyrrolyl orsubstituted phenyl or pyridyl containing one or two substituentsindependently selected from halo, alkyl and alkoxy, specifically,chloro, methyl and methoxy; W² is C₁-C₄ alkyl, C₂-C₄ alkynyl, C₃-C₆cycloalkyl, aryl, Het hydroxy, aryloxy-, C₁-C₄ alkoxy-, —OCOC₁-C₄ alkyl,—OCOaryl, or —NR^(W1)R^(W2), where R^(W1) and R^(W2) are independently Hor C₁-C₄ alkyl or taken together with the nitrogen to which they areattached form a 4-7 membered heterocyclic ring, which may optionallycontain one or more additional heteroatoms selected form N, O and S; W³is H or C₁-C₄ alkyl; or a pharmaceutically acceptable salt or hydratethereof.
 18. The compound according to claim 1, wherein X is chloro,bromo, cyano, carboxy-, methylcarboxy-, hydroxy, methoxy, methyl,trifluoromethyl, 1,3-dihydroxy-prop-2-yl (—CH(CH₂OH)₂, isopropyl,n-butyl, isobutyl, 2,2-dimethylpropyl, phenylcarbonyl, triazolyl,tetrazolyl, —NH₂, —NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH₂CH₂CH₂CH₃,—NHCH₂CH₂CH₂CH₂CH₂CH₃, —NHCH₂C(CH₃)₃, —NHCH₂CH(CH₃)₂, —NHCH₂CH₂CH(CH₃)₂,—NH-cyclopentyl, —NH-phenyl, —NHCH2-cyclopropyl, —NHCH(CH₃)₂, —NHCH₂CF₃,—N(CH₃)₂, —N(CH₂CH₃)₂, —NHCH(CH₂CH₃)₂, —NHCH₂CH(CH₂CH₃)₂, —NHCH₂CH₂OH,—NHCH₂CO₂H, —N(CH₃)CH₂CO₂H, —NHC(CH₃)₂CO₂H, —NHCH(CH₃)CO₂H,—(R)—NHCH(CH₃)CO₂H, —(S)—NHCH(CH₃)CO₂H, —NHCH₂-1H-imidazol-2-yl,—NHCH₂-(1-CH₃-iimidazol-2-yl, —NH-(pyrimidin-2-yl), -morpholin-4-yl,-thiomorpholin-4-yl, -piperidin-1-yl, -piperidin-1-yl-(4-carboxylicacid), -piperidin-1-yl-(4-acetic acid), -piperidin-4-yl-(1-acetic acid),-2,5-dimethyl-pyrrol-1-yl, -pyrrolidin-1-yl,—((R)-2-CO₂H-pyrrolidin-1-yl), —((S)-2-CO₂H-pyrrolidin-1-yl),-piperazin-1-yl, -(4-methyl-piperazin-1-yl), -piperazin-1-yl-(4-aceticacid), —NHCH₂-(5-bromo-thien-2-yl), —NHCH₂-1H-imidazol-2-yl,—NHCH₂-(1-methyl-imidazol-2-yl, —NHCOCH₃, —N(CH₃)COCH₃, —NHCO₂C(CH₃)₃,—NHCOCH₂CH₃, —NHCOC(CH₃)₂, —NHCO-furan-2-yl, —N(CH₃)CO-furan-2-yl,—NHCO-thien-2-yl, —NHCO-cyclopropyl, —NHCO-(5-bromo-thien-2-yl,—NHCO-(2,5-dimethyl-pyrrol-3-yl), —NHSO₂CH₃, —N(CH₃)SO₂CH₃, —NHSO₂CF₃,—NHSO₂phenyl, —N(CH₃)SO₂phenyl, —NHSO₂CH₂CH₃, —NHSO₂CH₂CF₃,—NHSO₂CH₂CH₂CH₃, —NHSO₂CH(CH₃)₂,—NHCONH(2-chlorophenyl),—N(CH₃)CONH(3,5-dimethoxyphenyl), —N(CH₃)CONH(2-chlorophenyl),—N(CH₃)CO-(benzo[1,3]diox-5-yl), —SO₂NHCH₃, and —SO₂N(CH₃)₂; p is 0, 1or 2; R¹ and R² are H C₁-C₄ alkyl or R¹ and R² together with the carbonto which they are attached form a 3, 4 or 5 membered carbocyclic ring; Zis CH of N; k is 0 or k is 1 and R³ is methyl, trifluoromethyl, chloroor methoxy; n is 3 and R⁴ and R⁵ are independently selected from H andmethyl; Y is —O— or —C(R⁴)(R⁵)—; q is 1; R⁸ and R⁹ are each H; Q is2-chloro-3-(trifluoromethyl)phenyl, 3-methyl-4-fluoro-phenyl,4-tert-butyl-phenyl, 4-(methylthio)phenyl, 2,4,5-trifluoro-phenyl,4-isopropyl-phenyl, 5-(piperidin-1-yl)-furan-2-yl, benzo[1,3]diox-5-yl,or 2,3-dihydrobenzo[1,4]dioxin-6-yl; t is 0 or 1; m is 0 or 1; R⁶ and R⁷are independently selected from H and methyl; W¹ is phenyl, naphth-1-yl,pyrid-2-yl, 4-methyl-pyrid-2-yl, thien-2-yl, thien-3-yl, pyrrol-2-yl,2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-methoxyphenyl, or4-methoxyphenyl; W² is methyl, ethyl, ethynyl, isopropyl, n-butyl,2-methylpropyl, trifluorormethyl, cyclohexyl, unsubstituted phenyl,hydroxy, methoxy, phenoxy, dimethylamino, morpholin-4-yl,phenylcarbonyloxy, or methylcarbonyloxy; W³ is H or methyl; or apharmaceutically acceptable salt or hydrate thereof.
 19. The compoundaccording to claim 1, wherein W¹ and W² are not each independently C₃-C₈cycloalkyl or aryl or W³ is not H or any one of R⁶ or R⁷ is not H or R⁸and R⁹ are each C₁-C₄ alkyl when: X is COOR¹⁰; Z is CH or CR³ and k is0-4 or Z is N and k is 0-3; p is 0-8; n is 3; q is 0 or 1; Q is selectedfrom optionally unsubstituted or substituted C₃-C₈ cycloalkyl, phenyland monocyclic Het; each R¹ and R² is independently selected from H,C₁-C₆ alkyl, —OH, —O—C₁-C₆ alkyl, —SH, and —S—C₁-C₆ alkyl; and each R³is the same or different and is independently selected from halo, cyano,nitro, —CONR¹²R¹³, —COR¹⁴, —SR¹¹, —SO₂R¹¹, —SOR¹⁴, —OCOR¹⁴ andoptionally unsubstituted or substituted C₁-C₆ alkyl, C₃-C₆ alkenyl, -5-6membered-Het, —C₀-C₆ alkyl-CO₂R¹¹, or —C₀-C₆ alkyl-NR¹²R¹³.
 20. Acompound selected from:2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2,2-dephenylethyl)amino]propoxy}phenyl)-ethanol;2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]propoxy}-phenyl)aceticacid, N-oxide;(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]propoxy}-bromobenzene;(4-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]propoxy}-bromobenzene;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenylethyl)-{3-[3-(1,2,4-triazol-3-ylmethyl)-phenoxy]-propyl}-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[3-(1,2,3,4-tetrazol-5-ylmethyl)-phenoxy]-propyl}-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2-cyclohexyl-2-phenyl-ethyl)-{3-[3-(1,2,3,4-tetrazol-5-ylmethyl)-phenoxy]-propyl}-amine;(S)-2-Chloro-3-trifluoromethyl-benzyl)-(2-phenyl-propyl)-{3-[3-(1,2,3,4-tetrazol-3-ylmethyl)-phenoxy]-propyl}-amine;(R)-(2-Chloro-3-trifluoromethyl-benzyl)-(2-phenyl-propyl)-{3-[3-(1,2,3,4-tetrazol-3-ylmethyl)-phenoxy]-propyl}-amine;(S)-2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2-phenyl-propyl)amino]propoxy}-phenyl)aceticacid;(R)-2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2-phenyl-propyl)amino]propoxy}-phenyl)aceticacid;Chloro-3-(trifluoromethyl)benzyl]naphthalen-1-ylmethyl-amino]propoxy}-phenyl)aceticacid;2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl]-benzylamino]propoxy}-phenyl)aceticacid;2-(3-{3-[[2-Chloro-3-(trifluoromethyl)-benzyl]phenethylamino]propoxy}-phenyl)aceticacid;2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2-hydroxy-2-phenyl-ethyl)amino]propoxy}-phenyl)aceticacid;2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2-acetoxy-2-phenyl-ethyl)amino]propoxy}-phenyl)aceticacid;2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2-phenoxy-2-phenyl-ethyl)amino]propoxy}-phenyl)aceticacid; Benzoic acid2-[3-(3-carboxymethyl-phenoxy)-{2-chloro-3-(trifluoromethyl)benzyl}propylamino]-1-phenylethyl ester;(3-{3-[(2-Acetoxy-2-phenyl-ethyl)-(2-chloro-3-trifluoromethyl-benzyl)-amino]-propoxy}-phenyl)-acetcacid methyl ester; Benzoic acid2-[3-(3-methoxycarbonylmethyl-phenoxy){2-chloro-3-(trifluoromethyl)benzyl}propylamino]-1-phenylethyl ester;(3-{4-[(2-Chloro-3-(trifluoromethyl)benzyl)-(2,2-diphenylethyl)-amino]butyl}phenyl)-aceticacid;(3-{3-[(4-Fluoro-3-methyl-benzyl)-((R)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-aceticacid;(3-{3-[Benzo[1,3]dioxol-5-ylmethyl-((R)-2-phenyl-propyl)-amino]-propoxy}phenyl)-aceticacid;(3-{3-[(4-tert-Butyl-benzyl)-((R)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-aceticacid;(3-{3-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-((R)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-aceticacid;(3-{3-[(4-Methylsulfanyl-benzyl)-((R)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-aceticacid;(3-{3-[((R)-2-Phenyl-propyl)-(2,4,5-trifluoro-benzyl)-amino]-propoxy}-phenyl)-aceticacid;(3-{3-[((R)-2-Phenyl-propyl)-(5-piperidin-1-yl-furan-2-ylmethyl)-amino]-propoxy}-phenyl)-aceticacid;(3-{3-[(4-Isopropyl-benzyl)-((R)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-aceticacid;2-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-propane-1,3-diol;N-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-carbamicacid tert-butyl ester;3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethylamino]-propoxy}-phenylamine;N-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-acetamide;Furan-2-carboxylic acidN-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-amide;N-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-methanesulfonamide;N-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-benzenesulfonamide;1-(2-Chloro-phenyl)-3-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-urea;N-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-N-methyl-amine;N-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-N-methyl-acetamide;Furan-2-carboxylic acidN-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-N-methyl-amide;N-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-N-methyl-methanesulfonamide;(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-N-methyl-benzenesulfonamide;3-(2-Chloro-phenyl)-1-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-1-methyl-urea;Benzo[1,3]dioxole-5-carboxylic acidN-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-N-methyl-amide;1-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-3-(3,5-dimethoxy-phenyl)-1-methyl-urea;Propane-1-sulfonic acid(5-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-2-methyl-phenyl)-amide;3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-2-methyl-phenylamine;2-Chloro-5-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenylamine;3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-cyclopentyl-amine;(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-isopropyl-amine;Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-ethyl-amine;(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-(3-methyl-butyl)-amine;(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-isobutyl-amine;(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-(2,2,2-trifluoroethyl)-amine;(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-cyclopropylmethy-1-amine;(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-(2-ethyl-butyl)-amine;(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-(2,2-dimethyl-propyl)-amine;(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-hexyl-amine;Butyl-(3-{3[(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-amine;[1-(3-{3-[(2-Chloro-3-(trifluoromethyl)-benzyl)-(2,2-diphenylethyl)-amino]-propoxy}-phenyl-piperidine-4-carboxylicacid;[1-(3-{3-[(2-Chloro-3-(trifluoromethyl)-benzyl)-(2,2-diphenylethyl)-amino]-propoxy}-phenyl-piperidine-4-yl-aceticacid;[4-(3-{3-[(2-Chloro-3-(trifluoromethyl)-benzyl)-(2,2-diphenylethyl-amino]-propoxy}-phenyl)-piperidin-1-yl]-aceticacid;rac-±-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(trifluoro-phenyl-propyl)-amino]-propoxy}-phenyl)-aceticacid;rac-±-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2-dimethylamino-2-phenyl-ethyl)-amino]-propoxy}-phenyl)-aceticacid;rac-±-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2-morpholin-4-yl-2-phenyl-ethyl)-amino]-propoxy}-phenyl)-aceticacid;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(6-morpholin-4-yl-pyridin-2-yloxy)-propyl]-amine;[3-(6-Chloro-pyridin-2-yloxy)-propyl]-(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[6-(4-methyl-piperazin-1-yl)-pyridin-2-yloxy]-propyl}-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(6-piperazin-1-yl-pyridin-2-yloxy)-propyl]-amine;[4-(6-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-pyridin-2-yl)-piperazin-1-yl]-aceticacid;2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl]((S)-2-phenyl-propyl)amino]-(R)-1-methyl-propoxy}-phenyl)aceticacid;2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl]((S)-2-phenyl-propyl)amino]-(R)-1-methyl-propoxy}-phenyl)ethanol;2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl]((S)-2-phenyl-propyl)amino]-(R)-2-methyl-propoxy}-phenyl)aceticacid;2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl]((S)-2-phenyl-propyl)amino]-(R)-2-methyl-propoxy}-phenyl)ethanol;2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl]((R)-2-phenyl-propyl)amino]-(R)-2-methyl-propoxy}-phenyl)aceticacid;2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl]((R)-2-phenyl-propyl)amino]-(R)-2-methyl-propoxy}-phenyl)ethanol;(R)-2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]-2-methyl-propoxy}-phenyl)ethanol;3-{3-[(3-Chloro-2-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy-N,N-dimethyl-benzenesulfonamide;Cyclopropanecarboxylic acid3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-benzylamide;N-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-benzyl)-isobutyramide;Acetic acid(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-benzylcarbamoyl)-methylester;N-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-benzyl)-propionamide;2,5-Dimethyl-2-H-pyrazole-3-carboxylic acid3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-benzylamide;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-(3-o-tolyloxy-propyl)-amine;2-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-benzonitrile;[3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}benzonitrile;[3-(3-Chloro-phenoxy)-propyl]-(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(2-methoxy-phenoxy)-propyl]-amine;[3-(2-Chloro-phenoxy)-propyl]-(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-(3-phenoxy-propyl)-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-isopropyl-phenoxy)-propyl]-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(4-methoxy-phenoxy)-propyl]-amine;3-{3-[(Chloro-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenol;2-{3-[(Chloro-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenol;3-{3-[(Chloro-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenylamine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-trifluoromethyl-phenoxy)-propyl]-amine;1-(3-{3-[(Chloro-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-ethanone;(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-phenyl-amine;[3-(Benzo[1,3]dioxol-5-yloxy)-propyl]-(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-(3-m-tolyloxy-propyl)-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-methoxy-phenoxy)-propyl]-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-isobutyl-phenoxy)-propyl]-amine;[3-(3-Butyl-phenoxy)-propyl]-(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amine;(2-Chloro-3-trifluoromethyl-benzyl)-{3-[3-(2,2-dimethyl-propyl)-phenoxy]-propyl}-(2,2-diphenyl-ethyl)-amine;(4-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-benzyl)-methyl-amine;(2-Chloro-3-trifluoromethyl-benzyl)-[3-(4-dimethylaminomethyl-phenoxy)-propyl]-(2,2-diphenyl-ethyl)-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(4-morpholin-4-ylmethyl-phenoxy)-propyl]-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[4-(4-methyl-piperazin-1-ylmethyl)-phenoxy]-propyl}-amine;(3-{3-[(Chloro-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-benzyl)-methyl-amine;(2-Chloro-3-trifluoromethyl-benzyl)-[3-(3-dimethylaminomethyl-phenoxy)-propyl]-(2,2-diphenyl-ethyl)-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-morpholin-4-ylmethyl-phenoxy)-propyl]-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[3-(4-methyl-piperazin-1-ylmethyl)-phenoxy]-propyl}-amine;(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-benzyl)-isopropyl-amine;{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-4-trifluoromethyl-phenylamine;{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-4-methyl-phenylamine;Ethanesulfonic acid(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-4-methyl-phenyl)-amide;Propane-2-sulfonic acid(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-4-methyl-phenyl)-amide;Methanesulfonic acid(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-4-methyl-phenyl)-amide;2,2,2-Trifluoro-ethanesulfonic acid(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-4-methyl-phenyl)-amide;Ethanesulfonic acid(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-phenyl)-amide;2,2,2-Trifluoro-ethanesulfonic acid(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-phenyl)-amide;N-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-phenyl)-1,1,1-trifluoro-methanesulfonamide;Propane-2-sulfonic acid(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-phenyl)-amide;{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-4-methoxy-phenylamine;Ethanesulfonic acid(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-4-methoxy-phenyl)-amide;(2-Chloro-3-trifluoromethyl-benzyl)-{3-[3-(2-morpholin-4-yl-ethyl)-phenoxy]-propyl}-((S)-2-phenyl-propylamine;(2-Chloro-3-trifluoromethyl-benzyl)-{3-[3-(2-ethylamino-ethyl)-phenoxy]-propyl}-((S)-2-phenyl-propyl)-amine;(3-{(R)-3-[(2-Chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-amino]-butoxy}-phenyl)-aceticacid;(3-{(S)-3-[(2-Chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-amino]-butoxy}-phenyl)-aceticacid;2-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-ethanol;2-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-2-methyl-propionicacid;2-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-((R)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-2-methyl-propionicacid;(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2-thiophen-3-yl-propyl)-amino]-propoxy}-phenyl)-aceticacid;2-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2-thiophen-3-yl-propyl)-amino]-propoxy}-phenyl)-ethanol;(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2-thiophen-2-yl-propyl)-amino]-propoxy}-phenyl)-aceticacid;(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2-pyridin-2-yl-propyl)-amino]-propoxy}-phenyl)-aceticacid;[3-(3-{(2-Chloro-3-trifluoromethyl-benzyl)-[2-(4-methyl-pyridin-2-yl)-propyl]-amino}-propoxy)-phenyl]-aceticacid;[3-(3-{(2-Chloro-3-trifluoromethyl-benzyl)-[3,3,3-trifluoro-2-(1H-pyrrol-2-yl)-propyl]-amino}-propoxy)-phenyl]-aceticacid;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-(3-{3-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenoxy}-propyl)-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[3-(2-methylamino-ethyl)-phenoxy]-propyl}-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-{2-[(1H-imidazol-2-ylmethyl)-amino]-ethyl}-phenoxy)-propyl]-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[3-(2-ethylamino-ethyl)-phenoxy]-propyl}-amine;[3-(3-{2-[(5-Bromo-thiophen-2-ylmethyl)-amino]-ethyl}-phenoxy)-propyl]-(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-{2-[(thiophen-2-ylmethyl)-amino]-ethyl}-phenoxy)-propyl]-amine;(2-Chloro-3-trifluoromethyl-benzyl)-{3-[3-(2-dimethylamino-ethyl)-phenoxy]-propyl}-(2,2-diphenyl-ethyl)-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[3-(2-pyrrolidin-1-yl-ethyl)-phenoxy]-propyl}-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[3-(2-morpholin-4-yl-ethyl)-phenoxy]-propyl}-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{(R)-1-methyl-3-[3-(2-morpholin-4-yl-ethyl)-phenoxy]-propyl}-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{(R)-2-methyl-3-[3-(2-morpholin-4-yl-ethyl)-phenoxy]-propyl}-amine;{3-[3-(2-Amino-ethyl)-phenoxy]-propyl}-(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amine;[2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-ethyl]-isopropyl-amine;[2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-ethyl]-propyl-amine;2-[2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-ethylamino]-ethanol;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-{2-[(1-methyl-1H-imidazol-2-ylmethyl)-amino]-ethyl}-phenoxy)-propyl]-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[3-(2-thiomorpholin-4-yl-ethyl)-phenoxy]-propyl}-amine;[2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-ethylamino]-aceticacid;[2-(3-{(R)-3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-butoxy}-phenyl)-ethylamino]-aceticacid;{[2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-ethyl]-methyl-amino}-aceticacid;2-[2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-ethylamino]-2-methyl-propionicacid;(S)-2-[2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-ethylamino]-propionicacid;(R)-1-[2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-ethyl]-pyrrolidine-2-carboxylicacid;(S)-1-[2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-ethyl]-pyrrolidine-2-carboxylicacid;[2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-ethyl]-pyrimidin-2-yl-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-morpholin-4-yl-phenoxy)-propyl]-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-piperidin-1-yl-phenoxy)-propyl]-amine;(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-diethyl-amine;(2-Chloro-3-trifluoromethyl-benzyl)-{3-[3-(2,5-dimethyl-pyrrol-1-yl)-phenoxy]-propyl}-(2,2-diphenyl-ethyl)-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-piperazin-1-yl-phenoxy)-propyl]-amine;(2-Chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-[3-(3-piperazin-1-yl-phenoxy)-propyl]-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[(R)-2-methyl-3-(3-piperazin-1-yl-phenoxy)-propyl]-amine;[4-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-piperazin-1-yl]-aceticacid;[4-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-piperazin-1-yl]-aceticacid;[4-(3-((R)-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-methyl-propoxy}-phenyl)-piperazin-1-yl]-aceticacid;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[3-(4-methyl-piperazin-1-yl)-phenoxy]-propyl}-amine;(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-pyrrolidin-1-yl-phenoxy)-propyl]-amine;(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenylamino)-aceticacid;[(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-N-methyl-amino]-aceticacid;N-(2,2-Diphenylethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-[3-(2-methyl-2-aminopropyl)phenoxy]propylamine;N-(2,2-Diphenylethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-[2-hydroxymethyl]phenoxy)propylamine,N-(2,2-Diphenylethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-[2-hydroxy-2-methylpropyl]phenoxy)propylamine;N-(2,2-Diphenylethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-N-methylsulfonamidophenoxy)propylamine;N-(2-[2-Chlorophenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine;N-(2-[3-Chlorophenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine;N-(2-[4-Chlorophenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine;N-(2-[2-Methoxyphenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine;N-(2-[4-Methoxyphenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine;N-(2-Phenyl-4-methylpentyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine;N-(2-Phenylbutyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine;N-(2-[2-Methyl-2-phenyl]propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine;N-(2-Phenyl-3-methylbutyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine;N-(2-Phenylhexyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine;N-(2-Phenyl-3-butynyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine;(S)-N-(2-Phenyl-2-methoxyethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine;(R)-N-(2-Phenyl-2-methoxyethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine;(R)-N-(2-Phenyl-2-methoxyethyl)-N-2-chloro-3-trifluoromethylbenzyl)-3-(3-[2-hydroxy-2-methylpropyl]phenoxy)propylamine;1-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-cyclobutanecarboxylicacid;1-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-cyclopentanecarboxylicacid;1-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-cyclopropanecarboxylicacid; and a pharmaceutically acceptable salt or hydrate thereof.
 21. Thecompound according to claim 1, selected from:2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2,2-dephenylethyl)amino]propoxy}phenyl)-ethanol,(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenylethyl)-{3-[3-(1,2,4-triazol-3-ylmethyl)-phenoxy]-propyl}-amine,(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[3-(1,2,3,4-tetrazol-5-ylmethyl)-phenoxy]-propyl}-amine,(2-chloro-3-trifluoromethyl-benzyl)-(2-cyclohexyl-2-phenyl-ethyl)-{3-[3-(1,2,3,4-tetrazol-5-ylmethyl)-phenoxy]-propyl}-amine,2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl]-benzylamino]propoxy}-phenyl)aceticacid,2-(3-{3-[[2-chloro-3-(trifluoromethyl)-benzyl]phenethylamino]propoxy}-phenyl)aceticacid,2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2-hydroxy-2-phenyl-ethyl)amino]propoxy}-phenyl)aceticacid,2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2-acetoxy-2-phenyl-ethyl)amino]propoxy}-phenyl)aceticacid,2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2-phenoxy-2-phenyl-ethyl)amino]propoxy}-phenyl)aceticacid,(3-{3-[(2-acetoxy-2-phenylethyl)(2-chloro-3-trifluoromethyl-benzyl)-amino]-propoxy}-phenyl)-aceticacid methyl ester, benzoic acid2-[3-(3-methoxycarbonylmethyl-phenoxy){2-chloro-3-(trifluoromethyl)benzyl}propylamino]-1-phenylethyl ester,(3-{4-(2-chloro-3-trifluoromethyl)benzyl)-(2,2-diphenylethyl)-amino]butyl}phenyl)-aceticacid, furan-2-carboxylic acidN-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-amide,1-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-cyclobutanecarboxylicacid,N-(2,2-diphenylethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-[2-hydroxy-2-methylpropyl]phenoxy)propylamine,(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-{2-[(1H-imidazol-2-ylmethyl)-amino]-ethyl}-phenoxy)-propyl]-amine,N-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-methanesulfonamide,N-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-N-methyl-amine,[2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-ethylamino]-aceticacid,N-(2-[3-chlorophenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,[4-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-piperazin-1-yl]-aceticacid,(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[3-(4-methyl-piperazin-1-yl)-phenoxy]-propyl}-amine,[1-(3-{3-[(2-chloro-3-(trifluoromethyl)-benzyl)-(2,2-diphenylethyl)-amino]-propoxy}-phenyl-piperidine-4-carboxylicacid, and a pharmaceutically acceptable salt or hydrate thereof.
 22. Thecompound according to claim 1, selected from:(S)-(2-chloro-3-trifluoromethyl-benzyl)-(2-phenyl-propyl)-{3-[3-(1,2,3,4-tetrazol-3-ylmethyl)-phenoxy]-propyl}-amine,(R)-(2-chloro-3-trifluoromethyl-benzyl)-(2-phenyl-propyl)-{3-[3-(1,2,3,4-tetrazol-3-ylmethyl)-phenoxy]-propyl}-amine,(S)-2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2-phenyl-propyl)amino]propoxy}-phenyl)aceticacid,(R)-2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2-phenyl-propyl)amino]propoxy}-phenyl)aceticacid,(R)-1-[2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-ethyl]-pyrrolidine-2-carboxylicacid,(2-chloro-3-trifluoromethyl-benzyl)-{3-[3-(2-morpholin-4-yl-ethyl)-phenoxy]-propyl}-((S)-2-phenyl-propylamine,2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-2-methyl-propionicacid,(3-{(R)-3-[(2-chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-amino]-butoxy}-phenyl)-aceticacid,[4-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-piperazin-1-yl]-aceticacid,[4-(3-{(R)-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-methyl-propoxy}-phenyl)-piperazin-1-yl]-aceticacid, and a pharmaceutically acceptable salt or hydrate thereof.
 23. Apharmaceutical composition comprising a compound according to claim 1and a pharmaceutically acceptable carrier or diluent.
 24. A method forthe prevention or treatment of an LXR mediated disease or condition,wherein said disease or condition is selected from atherosclerosis andinflammation, comprising administering a therapeutically effectiveamount of the compound according to claim
 1. 25. The method according toclaim 24, comprising administering a therapeutically effective amount ofthe compound according to claim
 3. 26. The method according to claim 24,comprising administering a therapeutically effective amount of thecompound according to claim
 7. 27. The method according to claim 24,comprising administering a therapeutically effective amount of thecompound according to claim
 8. 28. The method according to claim 24,comprising administering a therapeutically effective amount of thecompound according to claim
 9. 29. The method according to claim 24,comprising administering a therapeutically effective amount of thecompound according to claim
 11. 30. The method according to claim 24,comprising administering a therapeutically effective amount of thecompound according to claim
 14. 31. The method according to claim 24,comprising administering a therapeutically effective amount of thecompound according to claim
 15. 32. The method according to claim 24,comprising administering a therapeutically effective amount of thecompound according to claim
 17. 33. The method according to claim 24,comprising administering a therapeutically effective amount of thecompound according to claim
 18. 34. The method according to claim 27,comprising administering a compound selected from:2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2,2-dephenylethyl)amino]propoxy}phenyl)-ethanol,(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenylethyl){3-[3-(1,2,4-triazol-3-ylmethyl)-phenoxy]-propyl}-amine,(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[3-(1,2,3,4-tetrazol-5-ylmethyl)-phenoxy]-propyl}-amine,(S)-(2-chloro-3-trifluoromethyl-benzyl)-(2-phenyl-propyl)-{3-[3-(1,2,3,4-tetrazol-3-ylmethyl)-phenoxy]-propyl}-amine,(R)-(2-chloro-3-trifluoromethyl-benzyl)-(2-phenyl-propyl)-{3-[3-(1,2,3,4-tetrazol-3-ylmethyl)-phenoxy]-propyl}-amine,(S-)-2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2-phenyl-propyl)amino]-propoxy}-phenyl)aceticacid,(R-)-2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2-phenyl-propyl)amino]-propoxy}-phenyl)aceticacid,2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2-acetoxy-2-phenyl-ethyl)amino]propoxy}-phenyl)aceticacid,(3-{3-[(2-acetoxy-2-phenyl-ethyl)-(2-chloro-3-trifluoromethyl-benzyl)-amino]-propoxy}-phenyl)-aceticacid methyl ester,(3-{4-[(2-chloro-3-(trifluoromethyl)benzyl)-(2,2-diphenylethyl)-amino]butyl}phenyl)-aceticacid,1-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-cyclobutanecarboxylicacid,N-(2,2-diphenylethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-[2-hydroxy-2-methylpropyl]phenoxy)propylamine,(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-{2-[(1H-imidazol-2-ylmethyl)-amino]-ethyl}-phenoxy)-propyl]-amine,N-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-methanesulfonamide,N-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-N-methyl-amine,[2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-ethylamino]-aceticacid,(R)-1-[2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-ethyl]-pyrrolidine-2-carboxylicacid, furan-2-carboxylic acidN-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-amide,N-(2-[3-chlorophenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine,(2-chloro-3-trifluoromethyl-benzyl)-{3-[3-(2-morpholin-4-yl-ethyl)-phenoxy]-propyl}-((S)-2-phenyl-propylamine,[4-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}phenyl)-piperazin-1-yl]-aceticacid,2-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-2-methyl-propionicacid,(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl){3-[3-(4-methyl-piperazin-1-yl)-phenoxy]-propyl}-amine,(3-{(R)-3-[(2-chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-amino]-butoxy}-phenyl)-aceticacid,[1-(3-{3-[(2-chloro-3-(trifluoromethyl)-benzyl)-(2,2-diphenylethyl)-amino]-propoxy}-phenyl-piperidine-4-carboxylicacid,[4-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-piperazin-1-yl]-aceticacid,[4-(3-{(R)-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-methyl-propoxy}-phenyl)-piperazin-1-yl]-aceticacid, and a pharmaceutically acceptable salt or hydrate thereof.
 35. Amethod for increasing reverse cholesterol transport, said methodcomprising administering a therapeutically effective amount of thecompound according to claim
 1. 36. A method for inhibiting cholesterolabsorption, said method comprising administering a therapeuticallyeffective amount of the compound according to claim 1.